nhaliday + genetic-load   62

What Does a “Normal” Human Genome Look Like? | Science
So, what have our first glimpses of variation in the genomes of generally healthy people taught us? First, balancing selection, the evolutionary process that favors genetic diversification rather than the fixation of a single “best” variant, appears to play a minor role outside the immune system. Local adaptation, which accounts for variation in traits such as pigmentation, dietary specialization, and susceptibility to particular pathogens is also a second-tier player. What is on the top tier? Increasingly, the answer appears to be mutations that are “deleterious” by biochemical or standard evolutionary criteria. These mutations, as has long been appreciated, overwhelmingly make up the most abundant form of nonneutral variation in all genomes. A model for human genetic individuality is emerging in which there actually is a “wild-type” human genome—one in which most genes exist in an evolutionarily optimized form. There just are no “wild-type” humans: We each fall short of this Platonic ideal in our own distinctive ways.
article  essay  org:nat  🌞  bio  biodet  genetics  genomics  mutation  genetic-load  QTL  evolution  sapiens  survey  summary  coding-theory  enhancement  signal-noise  egalitarianism-hierarchy  selection  tradeoffs  immune  recent-selection  perturbation  nibble  ideas  forms-instances 
november 2017 by nhaliday
Man's Future Birthright: Essays on Science and Humanity by H. J. Muller. - Reviewed by Theodosius Dobzhansky
Hermann J. Muller (1890-1967) was not only a great geneticist but a visionary full of messianic zeal, profoundly concerned about directing the evolutionary course of mankind toward what he believed a better future.
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july 2017 by nhaliday
Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders : Nature Genetics : Nature Research
Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.

https://en.wikipedia.org/wiki/Transmission_disequilibrium_test
study  biodet  behavioral-gen  genetics  population-genetics  QTL  missing-heritability  psychiatry  autism  👽  disease  org:nat  🌞  gwern  pdf  piracy  education  multi  methodology  wiki  reference  psychology  cog-psych  genetic-load  genetic-correlation  sib-study  hypothesis-testing  equilibrium  iq  correlation  intricacy  GWAS  causation  endo-exo  endogenous-exogenous 
july 2017 by nhaliday
The Genomic Health Of Ancient Hominins | bioRxiv
On a broad scale, hereditary disease risks are similar for ancient hominins and modern-day humans, and the GRS percentiles of ancient individuals span the full range of what is observed in present day individuals. In addition, there is evidence that ancient pastoralists may have had healthier genomes than hunter-gatherers and agriculturalists. We also observed a temporal trend whereby genomes from the recent past are more likely to be healthier than genomes from the deep past.

Gwern has interesting take (abstract is misleading): https://twitter.com/gwern/status/871061144152178688

here it is in conclusion (and cf Figure 3A):
The genomic health of ancient individuals appears to have improved over time (Figure 3B). This calls into question the idea that genetic load has been increasing in human populations (Lynch 2016). However, there exists a perplexing pattern: ancient individuals who lived within the last few thousand years have healthier genomes, on average, than present day humans.

http://www.pnas.org/content/early/2017/08/08/1703856114
After controlling for age, BMI, and other variables, knee OA prevalence was 2.1-fold higher (95% confidence interval, 1.5–3.1) in the postindustrial sample than in the early industrial sample. Our results indicate that increases in longevity and BMI are insufficient to explain the approximate doubling of knee OA prevalence that has occurred in the United States since the mid-20th century. Knee OA is thus more preventable than is commonly assumed, but prevention will require research on additional independent risk factors that either arose or have become amplified in the postindustrial era.
study  bio  preprint  sapiens  genetics  biodet  disease  health  history  antiquity  aDNA  farmers-and-foragers  agriculture  anthropology  GWAS  genetic-load  multi  twitter  social  commentary  gwern  dysgenics  trends  mutation  embodied  org:nat  obesity  public-health  epidemiology  🌞  science-anxiety 
june 2017 by nhaliday
Genomic analysis of family data reveals additional genetic effects on intelligence and personality | bioRxiv
methodology:
Using Extended Genealogy to Estimate Components of Heritability for 23 Quantitative and Dichotomous Traits: http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003520
Pedigree- and SNP-Associated Genetics and Recent Environment are the Major Contributors to Anthropometric and Cardiometabolic Trait Variation: http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005804

Missing Heritability – found?: https://westhunt.wordpress.com/2017/02/09/missing-heritability-found/
There is an interesting new paper out on genetics and IQ. The claim is that they have found the missing heritability – in rare variants, generally different in each family.

Some of the variants, the ones we find with GWAS, are fairly common and fitness-neutral: the variant that slightly increases IQ confers the same fitness (or very close to the same) as the one that slightly decreases IQ – presumably because of other effects it has. If this weren’t the case, it would be impossible for both of the variants to remain common.

The rare variants that affect IQ will generally decrease IQ – and since pleiotropy is the norm, usually they’ll be deleterious in other ways as well. Genetic load.

Happy families are all alike; every unhappy family is unhappy in its own way.: https://westhunt.wordpress.com/2017/06/06/happy-families-are-all-alike-every-unhappy-family-is-unhappy-in-its-own-way/
It now looks as if the majority of the genetic variance in IQ is the product of mutational load, and the same may be true for many psychological traits. To the extent this is the case, a lot of human psychological variation must be non-adaptive. Maybe some personality variation fulfills an evolutionary function, but a lot does not. Being a dumb asshole may be a bug, rather than a feature. More generally, this kind of analysis could show us whether particular low-fitness syndromes, like autism, were ever strategies – I suspect not.

It’s bad new news for medicine and psychiatry, though. It would suggest that what we call a given type of mental illness, like schizophrenia, is really a grab-bag of many different syndromes. The ultimate causes are extremely varied: at best, there may be shared intermediate causal factors. Not good news for drug development: individualized medicine is a threat, not a promise.

see also comment at: https://pinboard.in/u:nhaliday/b:a6ab4034b0d0

https://www.reddit.com/r/slatestarcodex/comments/5sldfa/genomic_analysis_of_family_data_reveals/
So the big implication here is that it's better than I had dared hope - like Yang/Visscher/Hsu have argued, the old GCTA estimate of ~0.3 is indeed a rather loose lower bound on additive genetic variants, and the rest of the missing heritability is just the relatively uncommon additive variants (ie <1% frequency), and so, like Yang demonstrated with height, using much more comprehensive imputation of SNP scores or using whole-genomes will be able to explain almost all of the genetic contribution. In other words, with better imputation panels, we can go back and squeeze out better polygenic scores from old GWASes, new GWASes will be able to reach and break the 0.3 upper bound, and eventually we can feasibly predict 0.5-0.8. Between the expanding sample sizes from biobanks, the still-falling price of whole genomes, the gradual development of better regression methods (informative priors, biological annotation information, networks, genetic correlations), and better imputation, the future of GWAS polygenic scores is bright. Which obviously will be extremely helpful for embryo selection/genome synthesis.

The argument that this supports mutation-selection balance is weaker but plausible. I hope that it's true, because if that's why there is so much genetic variation in intelligence, then that strongly encourages genetic engineering - there is no good reason or Chesterton fence for intelligence variants being non-fixed, it's just that evolution is too slow to purge the constantly-accumulating bad variants. And we can do better.
https://rubenarslan.github.io/generation_scotland_pedigree_gcta/

The surprising implications of familial association in disease risk: https://arxiv.org/abs/1707.00014
https://spottedtoad.wordpress.com/2017/06/09/personalized-medicine-wont-work-but-race-based-medicine-probably-will/
As Greg Cochran has pointed out, this probably isn’t going to work. There are a few genes like BRCA1 (which makes you more likely to get breast and ovarian cancer) that we can detect and might affect treatment, but an awful lot of disease turns out to be just the result of random chance and deleterious mutation. This means that you can’t easily tailor disease treatment to people’s genes, because everybody is fucked up in their own special way. If Johnny is schizophrenic because of 100 random errors in the genes that code for his neurons, and Jack is schizophrenic because of 100 other random errors, there’s very little way to test a drug to work for either of them- they’re the only one in the world, most likely, with that specific pattern of errors. This is, presumably why the incidence of schizophrenia and autism rises in populations when dads get older- more random errors in sperm formation mean more random errors in the baby’s genes, and more things that go wrong down the line.

The looming crisis in human genetics: http://www.economist.com/node/14742737
Some awkward news ahead
- Geoffrey Miller

Human geneticists have reached a private crisis of conscience, and it will become public knowledge in 2010. The crisis has depressing health implications and alarming political ones. In a nutshell: the new genetics will reveal much less than hoped about how to cure disease, and much more than feared about human evolution and inequality, including genetic differences between classes, ethnicities and races.

2009!
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june 2017 by nhaliday
Interview: Mostly Sealing Wax | West Hunter
https://soundcloud.com/user-519115521/greg-cochran-part-2
https://medium.com/@houstoneuler/annotating-part-2-of-the-greg-cochran-interview-with-james-miller-678ba33f74fc

- conformity and Google, defense and spying (China knows prob almost all our "secrets")
- in the past you could just find new things faster than people could reverse-engineer. part of the problem is that innovation is slowing down today (part of the reason for convergence by China/developing world).
- introgression from archaics of various kinds
- mutational load and IQ, wrath of khan neanderthal
- trade and antiquity (not that useful besides ideas tbh), Roman empire, disease, smallpox
- spices needed to be grown elsewhere, but besides that...
- analogy: caste system in India (why no Brahmin car repairmen?), slavery in Greco-Roman times, more water mills in medieval times (rivers better in north, but still could have done it), new elite not liking getting hands dirty, low status of engineers, rise of finance
- crookery in finance, hedge fund edge might be substantially insider trading
- long-term wisdom of moving all manufacturing to China...?
- economic myopia: British financialization before WW1 vis-a-vis Germany. North vs. South and cotton/industry, camels in Middle East vs. wagons in Europe
- Western medicine easier to convert to science than Eastern, pseudoscience and wrong theories better than bag of recipes
- Greeks definitely knew some things that were lost (eg, line in Pliny makes reference to combinatorics calculation rediscovered by German dude much later. think he's referring to Catalan numbers?), Lucio Russo book
- Indo-Europeans, Western Europe, Amerindians, India, British Isles, gender, disease, and conquest
- no farming (Dark Age), then why were people still farming on Shetland Islands north of Scotland?
- "symbolic" walls, bodies with arrows
- family stuff, children learning, talking dog, memory and aging
- Chinese/Japanese writing difficulty and children learning to read
- Hatfield-McCoy feud: the McCoy family was actually a case study in a neurological journal. they had anger management issues because of cancers of their adrenal gland (!!).

the Chinese know...: https://macropolo.org/casting-off-real-beijings-cryptic-warnings-finance-taking-economy/
Over the last couple of years, a cryptic idiom has crept into the way China’s top leaders talk about risks in the country’s financial system: tuo shi xiang xu (脱实向虚), which loosely translates as “casting off the real for the empty.” Premier Li Keqiang warned against it at his press conference at the end of the 2016 National People’s Congress (NPC). At this year’s NPC, Li inserted this very expression into his annual work report. And in April, while on an inspection tour of Guangxi, President Xi Jinping used the term, saying that China must “unceasingly promote industrial modernization, raise the level of manufacturing, and not allow the real to be cast off for the empty.”

Such an odd turn of phrase is easy to overlook, but it belies concerns about a significant shift in the way that China’s economy works. What Xi and Li were warning against is typically called financialization in developed economies. It’s when “real” companies—industrial firms, manufacturers, utility companies, property developers, and anyone else that produces a tangible product or service—take their money and, rather than put it back into their businesses, invest it in “empty”, or speculative, assets. It occurs when the returns on financial investments outstrip those in the real economy, leading to a disproportionate amount of money being routed into the financial system.
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may 2017 by nhaliday
Estimating the number of unseen variants in the human genome
To find all common variants (frequency at least 1%) the number of individuals that need to be sequenced is small (∼350) and does not differ much among the different populations; our data show that, subject to sequence accuracy, the 1000 Genomes Project is likely to find most of these common variants and a high proportion of the rarer ones (frequency between 0.1 and 1%). The data reveal a rule of diminishing returns: a small number of individuals (∼150) is sufficient to identify 80% of variants with a frequency of at least 0.1%, while a much larger number (> 3,000 individuals) is necessary to find all of those variants.

A map of human genome variation from population-scale sequencing: http://www.internationalgenome.org/sites/1000genomes.org/files/docs/nature09534.pdf

Scientists using data from the 1000 Genomes Project, which sequenced one thousand individuals from 26 human populations, found that "a typical [individual] genome differs from the reference human genome at 4.1 million to 5.0 million sites … affecting 20 million bases of sequence."[11] Nearly all (>99.9%) of these sites are small differences, either single nucleotide polymorphisms or brief insertion-deletions in the genetic sequence, but structural variations account for a greater number of base-pairs than the SNPs and indels.[11]

Human genetic variation: https://en.wikipedia.org/wiki/Human_genetic_variation

Singleton Variants Dominate the Genetic Architecture of Human Gene Expression: https://www.biorxiv.org/content/early/2017/12/15/219238
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may 2017 by nhaliday
Polymorphisms and Load | West Hunter
Anyhow, we now have some estimates of the relative influence of common variants on various traits (from recent Visscher-type papers) . The fraction of genetic variation that can be explained by common variants is about half for height and IQ, one-third for schizophrenia, one-quarter for BMI, and about one-fifth for personality, as measured by standard personality measures, which I don’t have much faith in. If I had to guess, and at this point I do, the more that trait variation is a deviation from the selective optimum, rather than being orthogonal to fitness, the more it is influenced by load.
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may 2017 by nhaliday
Soft sweeps are the dominant mode of adaptation in the human genome | bioRxiv
Detection of 2000 instances of recent human selection, half of which are specific to individual human populations, and many of which affect the central nervous system. Note this doesn’t cover polygenic selection, so it’s a very loose lower bound on how much recent human evolution there has been.

How Sweeps Get Soft: https://westhunt.wordpress.com/2011/09/29/how-sweeps-get-soft/
A puzzling finding from the search for selection in humans is the large number of apparently selected variants versus the apparent absence of high frequency selected regions and regions that have become fixed in our species.

Cochran, John Hawks, and I were involved in some of this work, and we all thought immediately without any discussion that the intermediate frequency sweeps must reflect heterozygote advantage.
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may 2017 by nhaliday
Typos | West Hunter
In a simple model, a given mutant has an equilibrium frequency μ/s, when μ is the mutation rate from good to bad alleles and s is the size of the selective disadvantage. To estimate the total impact of mutation at that locus, you multiply the frequency by the expected harm, s: which means that the fitness decrease (from effects at that locus) is just μ, the mutation rate. If we assume that these fitness effects are multiplicative, the total fitness decrease (also called ‘mutational load’) is approximately 1 – exp(-U), when U is where U=Σ2μ, the total number of new harmful mutations per diploid individual.

https://westhunt.wordpress.com/2012/10/17/more-to-go-wrong/

https://westhunt.wordpress.com/2012/07/13/sanctuary/
interesting, suggestive comment on Africa:
https://westhunt.wordpress.com/2012/07/13/sanctuary/#comment-3671
https://westhunt.wordpress.com/2012/07/14/too-darn-hot/
http://infoproc.blogspot.com/2012/07/rare-variants-and-human-genetic.html
https://westhunt.wordpress.com/2012/07/18/changes-in-attitudes/
https://westhunt.wordpress.com/2012/08/24/men-and-macaques/
I have reason to believe that few people understand genetic load very well, probably for self-referential reasons, but better explanations are possible.

One key point is that the amount of neutral variation is determined by the long-term mutational rate and population history, while the amount of deleterious variation [genetic load] is set by the selective pressures and the prevailing mutation rate over a much shorter time scale. For example, if you consider the class of mutations that reduce fitness by 1%, what matters is the past few thousand years, not the past few tens or hundreds of of thousands of years.

...

So, assuming that African populations have more neutral variation than non-African populations (which is well-established), what do we expect to see when we compare the levels of probably-damaging mutations in those two populations? If the Africans and non-Africans had experienced essentially similar mutation rates and selective pressures over the past few thousand years, we would expect to see the same levels of probably-damaging mutations. Bottlenecks that happened at the last glacial maximum or in the expansion out of Africa are irrelevant – too long ago to matter.

But we don’t. The amount of rare synonymous stuff is about 22% higher in Africans. The amount of rare nonsynonymous stuff (usually at least slightly deleterious) is 20.6% higher. The number of rare variants predicted to be more deleterious is ~21.6% higher. The amount of stuff predicted to be even more deleterious is ~27% higher. The number of harmful looking loss-of-function mutations (yet more deleterious) is 25% higher.

It looks as if the excess grows as the severity of the mutations increases. There is a scenario in which this is possible: the mutation rate in Africa has increased recently. Not yesterday, but, say, over the past few thousand years.

...

What is the most likely cause of such variations in the mutation rate? Right now, I’d say differences in average paternal age. We know that modest differences (~5 years) in average paternal age can easily generate ~20% differences in the mutation rate. Such between-population differences in mutation rates seem quite plausible, particularly since the Neolithic.
https://westhunt.wordpress.com/2016/04/10/bugs-versus-drift/
more recent: https://westhunt.wordpress.com/2017/06/06/happy-families-are-all-alike-every-unhappy-family-is-unhappy-in-its-own-way/#comment-92491
Probably not, but the question is complex: depends on the shape of the deleterious mutational spectrum [which we don’t know], ancient and recent demography, paternal age, and the extent of truncation selection in the population.
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may 2017 by nhaliday
The Issue that Time Forgot | West Hunter
Human population genetics in the 1960s was obsessed with the question of genetic load. Much of the motivation was concern about health consequences of radiation and nuclear weapons. We now know that radiation does bad things to organisms but that the mutation rate in mammals is nearly insensitive to the effects of ionizing radiation. No one knew that then. Popular concern about the issue was also pumped up by monster movies, which were everywhere on late night television. Does anyone remember Godzilla?

...

The key paper about load was published in 19582. Morton, Crow, and Muller showed that, under some simplifying assumptions, the regression of mortality (and on other traits like IQ) on the inbreeding coefficient could reveal the nature of our burden of mutations. In particular the negative logarithm of the rate, for example the infant mortality rate, should be linear in the inbreeding coefficient:

-ln(q) = A + Bf

where q is the mortality rate and f the inbreeding coefficient. Their important insight was the if our load is mostly deleterious recessives then the rate should increase rapidly with inbreeding. If, on the other hand, our load reflects a lot of balanced polymorphisms then the load should not increase very much with inbreeding. In particular the load ratio, B/A, ought to be something like 10 if there are a lot of deleterious recessives while something like 2 if there are a lot of balanced polymorphisms. A clear explanation of the the theory and the results availabe by the early 1970s can be found in the classic Cavalli and Bodmer text3.

The bottom line was that load ratios from human populations did not give a clear signal either way. A typical B/A ratio was something like 4. The interest in and optimism about load theory in 1960 had fizzled by 1970.

Today all those issues are back on the table in a big way. What is our burden of mutation? How many of our aches and pains and premature deaths are costs of balanced polymorphism? Unfortunately the whole toolkit of 50 years ago has been mostly forgotten by the current generation of human population geneticists. A shame.

- Harpending
west-hunter  scitariat  discussion  history  mostly-modern  electromag  bio  sapiens  genetics  population-genetics  genetic-load  mutation  kinship  reflection  stylized-facts  methodology  🌞 
april 2017 by nhaliday
Polygyny, Fertility, and Savings
For reasonable parameter values, I find that banning polygyny decreases fertility by 40 percent, increases savings by 70 percent, and increases output per capita by 170 percent.

also interesting:
Table A1 shows that almost all men do marry by age 50 in these countries. Thus the common perception that two wives for some men means no wives for equally many men is wrong. Since the sex ratios in most countries do not deviate much from one, one may wonder how such a high incidence of polygyny is possible. The answer to this puzzle lies in extremely high spousal age gaps coupled with high population growth (Tertilt 2004).7 Table 1 shows that the average age gap at first marriage is almost seven years in highly polygynous countries. Annual population growth in this area is 2.7 percent, which amounts to a 20 percent increase in cohort size over seven years. On average, each man could therefore marry 1.2 wives, or, put differently, 20 percent of the population could marry two wives.8

AFRICAN POLYGAMY: PAST AND PRESENT: http://voxeu.org/article/african-polygamy-past-and-present
https://www.dartmouth.edu/~neudc2012/docs/paper_3.pdf
https://twitter.com/FinchesofDarwin/status/903319029732884481
http://voxeu.org/article/understanding-long-run-effects-africa-s-slave-trades
This has led the authors to conclude that Africa’s history of the slave trades is the primary explanation for why today polygyny is much more prevalent in West Africa than in East Africa.
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april 2017 by nhaliday
Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0099009
https://twitter.com/dgmacarthur/status/904908988516585472
https://twitter.com/piper_jason/status/905128320869662720
http://www.biorxiv.org/content/early/2017/09/07/185330
https://www.technologyreview.com/s/608813/does-your-genome-predict-your-face-not-quite-yet/

http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1000451
Domestic dogs exhibit tremendous phenotypic diversity, including a greater variation in body size than any other terrestrial mammal. Here, we generate a high density map of canine genetic variation by genotyping 915 dogs from 80 domestic dog breeds, 83 wild canids, and 10 outbred African shelter dogs across 60,968 single-nucleotide polymorphisms (SNPs). Coupling this genomic resource with external measurements from breed standards and individuals as well as skeletal measurements from museum specimens, we identify 51 regions of the dog genome associated with phenotypic variation among breeds in 57 traits. The complex traits include average breed body size and external body dimensions and cranial, dental, and long bone shape and size with and without allometric scaling. In contrast to the results from association mapping of quantitative traits in humans and domesticated plants, we find that across dog breeds, a small number of quantitative trait loci (≤3) explain the majority of phenotypic variation for most of the traits we studied. In addition, many genomic regions show signatures of recent selection, with most of the highly differentiated regions being associated with breed-defining traits such as body size, coat characteristics, and ear floppiness. Our results demonstrate the efficacy of mapping multiple traits in the domestic dog using a database of genotyped individuals and highlight the important role human-directed selection has played in altering the genetic architecture of key traits in this important species.
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april 2017 by nhaliday
Interview Greg Cochran by Future Strategist
https://westhunt.wordpress.com/2016/08/10/interview/

- IQ enhancement (somewhat apprehensive, wonder why?)
- ~20 years to CRISPR enhancement (very ballpark)
- cloning as an alternative strategy
- environmental effects on IQ, what matters (iodine, getting hit in the head), what doesn't (schools, etc.), and toss-ups (childhood/embryonic near-starvation, disease besides direct CNS-affecting ones [!])
- malnutrition did cause more schizophrenia in Netherlands (WW2) and China (Great Leap Forward) though
- story about New Mexico schools and his children (mostly grad students in physics now)
- clever sillies, weird geniuses, and clueless elites
- life-extension and accidents, half-life ~ a few hundred years for a typical American
- Pinker on Harvard faculty adoptions (always Chinese girls)
- parabiosis, organ harvesting
- Chicago economics talk
- Catholic Church, cousin marriage, and the rise of the West
- Gregory Clark and Farewell to Alms
- retinoblastoma cancer, mutational load, and how to deal w/ it ("something will turn up")
- Tularemia and Stalingrad (ex-Soviet scientist literally mentioned his father doing it)
- germ warfare, nuclear weapons, and testing each
- poison gas, Haber, nerve gas, terrorists, Japan, Syria, and Turkey
- nukes at https://en.wikipedia.org/wiki/Incirlik_Air_Base
- IQ of ancient Greeks
- history of China and the Mongols, cloning Genghis Khan
- Alexander the Great vs. Napoleon, Russian army being late for meetup w/ Austrians
- the reason why to go into Iraq: to find and clone Genghis Khan!
- efficacy of torture
- monogamy, polygamy, and infidelity, the Aboriginal system (reverse aging wives)
- education and twin studies
- errors: passing white, female infanticide, interdisciplinary social science/economic imperialism, the slavery and salt story
- Jewish optimism about environmental interventions, Rabbi didn't want people to know, Israelis don't want people to know about group differences between Ashkenazim and other groups in Israel
- NASA spewing crap on extraterrestrial life (eg, thermodynamic gradient too weak for life in oceans of ice moons)
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march 2017 by nhaliday
De novo mutations in regulatory elements cause neurodevelopmental disorders | bioRxiv
De novo mutations in hundreds of different genes collectively cause 25-42% of severe developmental disorders (DD). The cause in the remaining cases is largely unknown. The role of de novo mutations in regulatory elements affecting known DD-associated genes or other genes is essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 DD patients. Here we show that de novo mutations in highly conserved fetal-brain active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant two-fold enrichment of recurrently mutated elements. We estimate that, genome-wide, de novo mutations in fetal-brain active elements are likely to be causal for 1-3% of patients without a diagnostic coding variant and that only a small fraction (<2%) of de novo mutations in these elements are pathogenic. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasise the importance of combining functional and evolutionary evidence to delineate regulatory causes of genetic disorders.
study  preprint  bio  sapiens  biodet  genetics  genomics  genetic-load  mutation  developmental  neuro  psychiatry  QTL  🌞  epidemiology  behavioral-gen 
march 2017 by nhaliday
Sustainability | West Hunter
There have been societies that functioned for a long time, thousands of years. They had sustainable demographic patterns. That means that they had enough children to replace themselves – not necessarily in every generation, but over the long haul. But sustainability requires more than that. Long-lived civilizations [ones with cities, literacy, governments, and all that] had a pattern of natural selection that didn’t drastically decrease intelligence – in some cases, one that favored it, at least in some subgroups. There was also ongoing selection against mutational accumulation – which meant that individuals with more genetic load than than average were significantly less likely to survive and reproduce. Basically, this happened through high child mortality, and in some cases by lower fitness in lower socioeconomic classes [starvation]. There was nothing fun about it.

Modern industrialized societies are failing on all three counts. Every population that can make a decent cuckoo clock has below-replacement fertility. The demographic pattern also selects against intelligence, something like one IQ point a generation. And, even if people at every level of intelligence had the same number of children, so that there was no selection against IQ, we would still be getting more and messed up, because there’s not enough selection going on to counter ongoing mutations.

It is possible that some country, or countries, will change in a way that avoids civilizational collapse. I doubt if this will happen by voluntary action. Some sort of technological solution might also arise – but it has to be soon.

Bruce Charlton, Victorian IQ, Episcopalians, military officers:
https://westhunt.wordpress.com/2013/05/09/sustainability/#comment-13188
https://westhunt.wordpress.com/2013/05/09/sustainability/#comment-13207
Again, I don’t believe a word of it. As for the declining rate of innovation, you have to have a really wide-ranging understanding of modern science and technology to have any feeling for what the underlying causes are. I come closer than most, and I probably don’t know enough. You don’t know enough. Let me tell you one thing: if genetic potential IQ for IQ had dropped 1 std, we’d see the end of progress in higher mathematics, and that has not happened at all.

Moreover, the selective trends disfavoring IQ all involve higher education among women and apparently nothing else – a trend which didn’t really get started until much more recently.

Not long enough, nor is dysgenic selection strong enough.

ranting on libertarians:
https://westhunt.wordpress.com/2013/05/09/sustainability/#comment-13348
About 40% of those Americans with credit cards keep a balance on their credit cards and pay ridiculous high interest. But that must be the right decision!
https://westhunt.wordpress.com/2013/05/09/sustainability/#comment-13499
” then that is their decision” – that’s fucking obvious. The question is whether they tend to make decisions that work very well – saying ‘that is their decision” is exactly the kind of crap I was referring to. As for “they probably have it coming” – if I’m smarter than you, which I surely am, using those smarts to rook you in every possible way must be just peachy. In fact, I’ll bet I could manage it even after warning you in advance.

On average, families in this country have paid between 10% and 14% of their income in debt service over the past few decades. That fraction averages considerably higher in low-income families – more like 18%. A quarter of those low income families are putting over 40% of their income into debt service. That’s mostly stuff other than credit-card debt.

Is this Straussian?

hmm:
Examining Arguments Made by Interest Rate Cap Advocates: https://www.mercatus.org/system/files/peirce_reframing_ch13.pdf

https://twitter.com/tcjfs/status/964972690435133440
https://archive.is/r34J8
Interest rate caps on $1,000 installment loans, by US state, today and in 1935
west-hunter  civilization  dysgenics  fertility  legacy  risk  mutation  genetic-load  discussion  rant  iq  demographics  gnon  sapiens  trends  malthus  leviathan  long-short-run  science-anxiety  error  biodet  duty  s:*  malaise  big-picture  debt  randy-ayndy  recent-selection  demographic-transition  order-disorder  deep-materialism  🌞  age-generation  scitariat  rhythm  allodium  behavioral-gen  nihil  zeitgeist  rot  the-bones  prudence  darwinian  flux-stasis  counter-revolution  modernity  microfoundations  multi  poast  civil-liberty  is-ought  track-record  time-preference  temperance  patience  antidemos  money  compensation  class  coming-apart  pro-rata  behavioral-econ  blowhards  history  early-modern  britain  religion  christianity  protestant-catholic  gender  science  innovation  frontier  the-trenches  speedometer  military  elite  optimate  data  intervention  aphorism  alt-inst  ethics  morality  straussian  intelligence  class-warfare  authoritarianism  hari-seldon  interests  crooked  twitter  social  back 
march 2017 by nhaliday
A Resolution of the Mutation Load Paradox in Humans
It has been argued that the mutation load, the proportional reduction in population mean fitness relative to the fitness of an idealized mutation-free individual, allows a theoretical prediction of the proportion of individuals in the population that fail to reproduce as a consequence of these harmful mutations. Application of this theory to humans implies that at least 88% of individuals should fail to reproduce and that each female would need to have more than 16 offspring to maintain population size. This prediction is clearly at odds with the low reproductive excess of human populations. Here, we derive expressions for the fraction of individuals that fail to reproduce as a consequence of recurrent deleterious mutation (φ) for a model in which selection occurs via differences in relative fitness, such as would occur through competition between individuals. We show that φ is much smaller than the value predicted by comparing fitness to that of a mutation-free genotype. Under the relative fitness model, we show that φ depends jointly on U and the selective effects of new deleterious mutations and that a species could tolerate 10’s or even 100’s of new deleterious mutations per genome each generation.

Mutation load under additive fitness effects: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957254/
pdf  study  org:nat  bio  sapiens  evolution  genetics  population-genetics  selection  mutation  genetic-load  🌞  models  EEA  distribution  deep-materialism  science-anxiety  multi 
march 2017 by nhaliday
Social Epistasis Amplifies the Fitness Costs of Deleterious Mutations, Engendering Rapid Fitness Decline Among Modernized Populations | SpringerLink
- Michael A. Woodley

We argue that in social species, interorganismal gene-gene interactions, which in previous literatures have been termed social epistasis, allow genomes carrying deleterious mutations to reduce via group-level pleiotropy the fitness of others, including noncarriers. This fitness reduction occurs by way of degradation of group-level processes that optimize the reproductive ecology of a population for intergroup competition through, among other mechanisms, suppression of free-riding.

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Fitness indicators theory (Houle 2000; Miller 2000) predicts that the behavioral and physiological condition of prospective partners strongly influences female mate choice in particular, as these constitute honest indicators of underlying genetic quality. Furthermore, as deleterious mutations are pleiotropic (i.e., they can influence the development of multiple traits simultaneously), they are a source of genetic correlation among diverse behavioral and physiological domains, yielding a latent general fitness factor( f ). This optimizes the efficiency of sexual selection, as selection for quality with respect to one domain will increase the probability of selection for quality “across the board” (Houle 2000; Miller 2000). If purifying selection is primarily cryptic—working by virtue of those lower in f simply being less successful in competition for mates and therefore producing fewer offspring relative to those higher in the factor—then considerably less reproductive failure is needed to solve the mutation load paradox (19% instead of 88% based on simulations in Leseque et al. 2012).

...

Theoretical work involving humans suggests a loss of intrinsic fitness of around 1% per generation in the populations of modernized countries (Lynch 2016; Muller 1950). Thus, these might yet be undergoing mutational meltdown, albeit very gradually (i.e., over the course of centuries)

...

An interesting observation is that the fitness of the populations of modernized nations does appear to be rapidly decreasing—although not in a manner consonant with the direct action of deleterious mutations on the fitness of individuals (as per the mutation load paradox).

...

Increased education has furthermore encouraged individuals to trade fertility against opportunities to enhance their social status and earning power, with the largest fitness losses occurring among those with high status who potentially carry fewer deleterious mutations (i.e., by virtue of possessing higher levels of traits that exhibit some sensitivity to mutation load, such as general intelligence; Spain et al. 2015; Woodley of Menie et al. 2016a). Hitherto not considered is the possibility that the demographic transition represents a potential change in the fitness characteristics of the group-level extended phenotype of modernized populations, indicating that there might exist pathways through which deleterious mutations that accumulate due to ecological mildness could pathologically alter fertility tradeoffs in ways that might account for the maladaptive aspects of the fertility transition (e.g., subreplacement fertility; Basten, Lutz and Scherbov, 2013).

...

Cooperation, though offering significant fitness benefits to individual organisms and groups, involves some costs for cooperators in order to realize mutual gains for all parties. Free riders are individuals that benefit from cooperation without suffering any of the costs needed to sustain it. Hence, free riders enjoy a fitness advantage relative to cooperators via the former’s parasitism on the latter.

...

The balance of selection can alternate between the different levels depending on the sorts of selective challenges that a population encounters. For example, group selection may operate on human populations during times of intergroup conflict (i.e., warfare), whereas during times of peace, selection may tend to favor the fitness of individuals instead (Woodley and Figueredo 2013; Wilson 2002). A major factor that seems to permit group-level selection to be viable under certain ecological regimes is the existence of free-rider controls, i.e., features of the group’s social ecology that curb the reproductive fitness of the carriers of “selfish” genetic variants (MacDonald 1994; Wilson 2002).

...

High-status individuals participate in the generation and vertical cultural transmission of free-rider controls—these take the form of religious and ideological systems which make a virtue out of behaviors that overtly benefit the group, and a vice out of those that only favor individual-level fitness, via the promotion of ethnocentrism, martyrdom, and displays of commitment (MacDonald 1994, 2009, 2010; Wilson 2002). Humans are furthermore equipped with specialized mental adaptations for coordinating as part of a group, such as effortful control—the ability to override implicit behavioral drives via the use of explicit processing systems, which allow them to regulate their behavior based on what is optimal for the group (MacDonald 2008). The interaction between individuals of different degrees of status, i.e., those that generate and maintain cultural norms and those who are merely subject to them, therefore constitutes a form of social epistasis, as the complex patterns of interactions among genomes that characterize human culture have the effect of regulating both individual- and group-level (via the curbing of free-riding) fitness (MacDonald 2009, 2010).

Mutations that push the behavior of high-status individuals away from the promotion of group-selected norms may promote a breakdown of or otherwise alter these social epistatic interactions, causing dysregulation of the group’s reproductive ecology. Behavioral changes are furthermore a highly likely consequence of mutation accumulation, as “behavior” (construed broadly) is a large potential target for new mutations (Miller 2000; Lynch 2016) 1 owing to the fact that approximately 84% of all genes in the human genome are involved in some aspect of brain development and/or maintenance (Hawrylycz et al. 2012).

Consistent with the theorized role of group-level (cultural) regulatory processes in the maintenance of fitness optima, positive correlations exist between religiosity (a major freerider control; MacDonald 1994; Wilson 2002) and fertility, both at the individual differences and cross-cultural levels (Meisenberg 2011). Religiosity has declined in modernized nations—a process that has gone hand-in-hand with the rise of a values system called postmaterialism (Inglehart 1977), which is characterized by the proliferation of individualistic, secular, and antihierarchical values (Welzel 2013). The holding of these values is negatively associated with fertility, both at the individual level (when measured as political liberalism; Goldstone et al. 2011) and across time and cultures (Inglehart and Appel 1989). The rise of postmaterialist values is also associated with increasingly delayed onset of reproduction (Klien 1990) which directly increases the (population) mutation load.

Pathological Altruism

Some of the values embodied in postmaterialism have been linked to the pathological altruism phenomenon, i.e., forms of altruism that damage the intended recipients or givers of largesse (Oakley et al. 2012; Oakley 2013). Virtues associated with altruism such as kindness, fidelity, magnanimity, and heroism, along with quasi-moral traits associated with personality and mental health, may be under sexual selection and might therefore be sensitive, through the f factor, to the deleterious effects of accumulating mutations (Miller 2007).

...

Another form of pathologically altruistic behavior that Oakley (2013) documents is self-righteousness, which may be increasing, consistent with secular trend data indicating elevated levels of self-regarding behavior among Western populations (sometimes called the narcissism epidemic; Twenge and Campbell 2009). This sort of behavior constitutes a key component of the clever silly phenomenon in which the embrace of counterfactual beliefs is used to leverage social status via virtue signaling (e.g., the conflation of moral equality among individuals, sexes, and populations with biological equality) (Dutton and van der Linden 2015; Charlton 2009; Woodley 2010). There may be a greater number of influential persons inclined to disseminate such beliefs, in that the prevalence of phenotypes disposed toward egoistic behaviors may have increased in Western populations (per Twenge and coworkers’ research), and because egoists, specifically Machiavellians and narcissists, appear advantaged in the acquisition of elite societal stations (Spurk et al. 2015).

[Do Bad Guys Get Ahead or Fall Behind? Relationships of the Dark Triad of Personality With Objective and Subjective Career Success: http://sci-hub.tw/http://journals.sagepub.com/doi/abs/10.1177/1948550615609735

After controlling for other relevant variables (i.e., gender, age, job tenure, organization size, education, and work hours), narcissism was positively related to salary, Machiavellianism was positively related to leadership position and career satisfaction, and psychopathy was negatively related to all analyzed outcomes.]

...

By altering cultural norms, elite egoists may encourage the efflorescence of selfish behaviors against which some older and once highly influential cultural systems acted. For example, Christianity in various forms strongly promoted personal sacrifice for the good of groups and proscribed egoistic behaviors (Rubin 2015), but has declined significantly in terms of cultural power following modernization (Inglehart 1977). Thus, it is possible that a feedback loop exists wherein deleterious mutation accumulation raises population levels of egoism, either directly or indirectly, via the breakdown of developmental constraints on personality canalization; the resultantly greater number of egoists are then able to exploit relevant personality traits to attain positions of sociocultural influence; and through these … [more]
study  speculation  models  biodet  bio  sapiens  evolution  genetic-load  paternal-age  the-monster  slippery-slope  society  social-structure  free-riding  coordination  EGT  dynamical  🌞  fertility  dysgenics  eh  self-control  obesity  altruism  mutation  multi  twitter  social  commentary  perturbation  gnon  new-religion  science-anxiety  population-genetics  biophysical-econ  hmm  discipline  autism  scitariat  clown-world  epidemiology  malaise  sociology  demographic-transition  blowhards  model-organism  nonlinearity  civilization  expression-survival  universalism-particularism  order-disorder  trends  deep-materialism  values  ideology  domestication  cohesion  christopher-lasch  scale  patho-altruism  social-capital  behavioral-gen  madisonian  chart  nihil  aristos  piracy  theos  cultural-dynamics  roots  zeitgeist  rot  the-bones  counter-revolution  pdf  modernity  microfoundations  video  presentation  religion  christianity  health  longevity  ethnocentrism  genetic-correlation  👽  instinct 
march 2017 by nhaliday
The Morality of Sperm Donation - Gwern.net
There is a third benefit. Surprisingly, sperm donor-assisted pregnancies result in 1/5th the number of birth defects as pregnancies in general. (The CDC tells me that the defect rate is 1 in 33 or ~3%, and that birth defects in 2006 directly killed 5,819 infants.) Much of this large benefit stems from the paternal age effect - older fathers’ sperm result in more birth defects, lowered IQ, linked to autism, etc. To the extent that a sperm donor donating displaces, at the margin, the conception of future offspring at an elder age, donation directly reduces birth defects and the other mentioned effects.

Indeed, given the mixed data on whether sperm count rates are falling with time and the more reliable data on the striking increases with paternal age of negative effects like birth defects or autism - perhaps due to increased mutations4 - it may be worthwhile even for non-donators to bank their sperm for later use. A quick perusal of one sperm bank’s prices suggests that a 20-year old could store a large sample of his sperm until he is 40 for ~$5000 with the ultimate artificial insemination adding <$4000 to the final cost; if this resulted in cutting the risk of his children being autistic by 30%, would it be worthwhile? Perhaps. It is worth considering.
ratty  gwern  hmm  sex  genetics  genetic-load  paternal-age  parenting  developmental  disease  data  effective-altruism  arbitrage  cost-benefit  analysis  faq  planning 
february 2017 by nhaliday
Neurodiversity | West Hunter
Having an accurate evaluation of a syndrome as a generally bad thing isn’t equivalent to attacking those with that syndrome. Being a leper is a bad thing, not just another wonderful flavor of humanity [insert hot tub joke] , but that doesn’t mean that we have to spend our spare time playing practical jokes on lepers, tempting though that is.. Leper hockey. We can cure leprosy, and we are right to do so. Preventing deafness through rubella vaccination was the right thing too – deafness sucks. And so on. As we get better at treating and preventing, humans are going to get more uniform – and that’s a good thing. Back to normalcy!

focus: https://westhunt.wordpress.com/2017/02/22/neurodiversity/#comment-88691
interesting discussion of mutational load: https://westhunt.wordpress.com/2017/02/22/neurodiversity/#comment-88793

https://westhunt.wordpress.com/2013/04/30/blurry/
I was thinking again about the consequences of having more small-effect deleterious mutations than average. I don’t think that they would push hard in a particular direction in phenotype space – I don’t believe they would make you look weird, but by definition they would be bad for you, reduce fitness. I remembered a passage in a book by Steve Stirling, in which our heroine felt as if her brain ‘was moving like a mechanism of jewels and steel precisely formed.’ It strikes me that a person with an extra dollop of this kind of genetic load wouldn’t feel like that. And of course that heroine did have low genetic load, being the product of millennia of selective breeding, not to mention an extra boost from the Invisible Crown.

https://westhunt.wordpress.com/2013/04/30/blurry/#comment-12769
Well, what does the distribution of fitness burden by frequency look like for deleterious mutations of a given fitness penalty?
--
It’s proportional to the mutation rate for that class. There is reason to believe that there are more ways to moderately or slightly screw up a protein than to really ruin it, which indicates that mild mutations make up most load in protein-coding sequences. More of the genome is made up of conserved regulatory sequences, but mutations there probably have even milder effects, since few mutations in non-coding sequences cause a serious Mendelian disease.

https://westhunt.wordpress.com/2013/04/30/blurry/#comment-12803
I have wondered if there was some sort of evolutionary tradeoff between muscles and brains over the past hundred thousand years through dystrophin’s dual role. There is some evidence of recent positive selection among proteins that interact with dystrophin, such as DTNBP1 and DTNA.

Any novel environment where higher intelligence can accrue more caloric energy than brute strength alone (see: the invention of the bow) should relax the selection pressure for muscularity. The Neanderthals didn’t fare so well with the brute strength strategy.
--
Sure: that’s what you might call an inevitable tradeoff, a consequence of the laws of physics. Just as big guys need more food. But because of the way our biochemistry is wired, there can be tradeoffs that exist but are not inevitable consequences of the laws of physics – particularly likely when a gene has two fairly different functions, as they often do.
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february 2017 by nhaliday
Prevalence and architecture of de novo mutations in developmental disorders : Nature
We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year.
pdf  study  org:nat  genetics  genomics  genetic-load  paternal-age  hmm  developmental  parenting  aging  biodet  GWAS  🌞  👽  science-anxiety  autism  epidemiology  deep-materialism  public-health  rot 
february 2017 by nhaliday
Links 2/17: Site Your Sources | Slate Star Codex
The United States not only does poorly on education benchmark PISA, but each decile of wealth also does poorly compared to equivalent deciles in other countries. I find this surprising. Does this torpedo the theory that each US ethnic group does as well as its foreign counterparts, and US underperformance is a Simpson’s Paradox on ethnic distribution?

Twitter: @EveryoneIsDril.

New Study Finds Performance-Enhancing Drugs For Chess. Okay, fine, just modafinil, which we already knew about, but the exact pattern is interesting. Modafinil makes people take longer to make their moves, but the moves are ultimately better. That suggests that its advantage is not increasing IQ per se, but in giving people the increased attention span/concentration to work harder on finding good moves. I think this elegantly ties together a lot of stuff into a good explanation of modafinil’s cognitive-enhancing properties.

New Zealand Wants To Know How Peter Thiel Became A Secret Citizen. Give up, New Zealand; Peter Thiel is a citizen of any country he wants to be a citizen of. Also: Peter Thiel Denies California Governor Run Despite Mysterious Group’s Backing.

I was going to link to the paper Physics Envy May Be Hazardous To Your Wealth, but the part that actually interested me is small enough that I’m just going to include it here as a jpg (h/t Julia Galef).

Nature: Prevalence And Architecture Of De Novo Mutations In Developmental Disorders. There’s been a lot of debate over paternal age effects, and this paper helps clarify that by actually counting people’s de novo mutations and finding that children of older fathers (and to a lesser degree older mothers) have more of them. I am not sure to what degree this answers the objection that fathers with worse genes will tend to get married later; my impression is that it’s circumstantial evidence against (de novo mutations are more specific to paternal age than just bad genes) but not complete disproof.

Psssst, kid, wanna buy a parasitic worm? Key quote: “Those who experience the ‘hookworm bounce’ tend to describe it as ‘feeling as if they are teenagers again'” (h/t pistachi0n).

New paper in Crime And Delinquency: “We find no evidence that the number of fatal police shootings either increased or decreased post-Ferguson. Claims to the contrary are based on weak analyses of short-term trends.” This is especially surprising in light of claims that increased inner-city crime is caused by police withdrawing in order to prevent further fatal shootings; if that’s the police’s plan, it doesn’t seem to be working very well.

Intranasal ghrelin vaccine prevents obesity in mice.

Gene drive testing thwarted when organisms quickly develop resistance. There goes that idea.

New poll: Majority of Europeans support banning Muslim immigration. It’s an Internet-based poll, which is always cause for suspicion, but they seem to be a reputable organization and not the sort of group whose results are 100% due to trolling by 4chan, plus it’s consistent with some other results. Still pretty shocking and an existential-terror-level reminder of partisan bubbles. Also: Rasmussen finds most Americans support Trump’s refugee ban order.

Closely related: M.G. Miles makes the case for banning Muslim immigration. Maybe the first person I have seen make this case in a principled way; everyone else just seems to be screaming about stuff and demanding their readers reinterpret it into argument form. Also, he uses the word “terrorism” zero times, which seems like the correct number of times for a case of this sort. This is what people should be debating and responding to. Rebuttals by Americans would probably want to start with the differences between Muslim immigrants to Europe and Muslim immigrants to the US – Miles discusses the European case, but by my understanding these are very different populations with very different outcomes).

Second Enumerations podcast: Grognor reading interesting essays.

SSRN: Extreme Protest Tactics Reduce Popular Support For Social Movements: “We find across three experiments that extreme protest tactics decreased popular support for a given cause because they reduced feelings of identification with the movement. Though this effect obtained in tests of popular responses to extreme tactics used by animal rights, Black Lives Matter, and anti-Trump protests (Studies 1-3), we found that self-identified political activists were willing to use extreme tactics because they believed them to be effective for recruiting popular support.” Cf. The Toxoplasma Of Rage. (h/t Dain)

The Cagots were an underclass of people in medieval France whom everyone hated, with various purity laws around how decent people weren’t allowed to associate with/marry/touch/go near them. In the 1500s, the Pope personally intervened to tell the French to stop persecuting them, but the French ignored him and persecuted them more than ever. As far as anyone can tell, they looked, spoke, and acted just like everyone else, and exactly how they became so despised is one of the minor mysteries of medieval history.
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february 2017 by nhaliday
Confounder Of The Day: How Sexy Your Parents Were | Slate Star Codex
- "paternal age effect" just a selection effect (men w/ issues end up having kids later due to difficulty finding a mate)
- one other suggested inconsistent explanation: spermatogenic selfish-gene effect
- interesting discussion of sperm freezing
yvain  ssc  psychiatry  medicine  aging  developmental  study  summary  genetic-load  hmm  biodet  causation  planning  parenting  paternal-age  disease  sex  gender  selfish-gene  gwern  confounding  EGT  epidemiology  null-result  sib-study  ratty  behavioral-gen  cooperate-defect 
february 2017 by nhaliday
Performance Trends in AI | Otium
Deep learning has revolutionized the world of artificial intelligence. But how much does it improve performance? How have computers gotten better at different tasks over time, since the rise of deep learning?

In games, what the data seems to show is that exponential growth in data and computation power yields exponential improvements in raw performance. In other words, you get out what you put in. Deep learning matters, but only because it provides a way to turn Moore’s Law into corresponding performance improvements, for a wide class of problems. It’s not even clear it’s a discontinuous advance in performance over non-deep-learning systems.

In image recognition, deep learning clearly is a discontinuous advance over other algorithms. But the returns to scale and the improvements over time seem to be flattening out as we approach or surpass human accuracy.

In speech recognition, deep learning is again a discontinuous advance. We are still far away from human accuracy, and in this regime, accuracy seems to be improving linearly over time.

In machine translation, neural nets seem to have made progress over conventional techniques, but it’s not yet clear if that’s a real phenomenon, or what the trends are.

In natural language processing, trends are positive, but deep learning doesn’t generally seem to do better than trendline.

...

The learned agent performs much better than the hard-coded agent, but moves more jerkily and “randomly” and doesn’t know the law of reflection. Similarly, the reports of AlphaGo producing “unusual” Go moves are consistent with an agent that can do pattern-recognition over a broader space than humans can, but which doesn’t find the “laws” or “regularities” that humans do.

Perhaps, contrary to the stereotype that contrasts “mechanical” with “outside-the-box” thinking, reinforcement learners can “think outside the box” but can’t find the box?

http://slatestarcodex.com/2017/08/02/where-the-falling-einstein-meets-the-rising-mouse/
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january 2017 by nhaliday
Oh, they were looking for their Missing Piece – spottedtoad
Assuming that the value of an offspring’s trait are determined by averaging the value of both parents and then adding some random error due to mutation or developmental noise, the ideal mate for each individual in the population isn’t the one that is closest to the ideal value, but one that is “complementary”- ie, equally distant from the ideal value, but from the opposite side.
ratty  unaffiliated  sapiens  evolution  sex  thinking  essay  genetic-load  speculation  spearhead  selection  models  equilibrium  parable  europe  mediterranean  history  literature  cartoons  wonkish  iron-age  myth  the-classics  assortative-mating  tails  extrema  matching  homo-hetero  complement-substitute  life-history  increase-decrease  signum  ecology  EGT 
january 2017 by nhaliday
The deleterious mutation load is insensitive to recent population history : Nature Genetics : Nature Research
contrary:
Distance from sub-Saharan Africa predicts mutational load in diverse human genomes: http://www.pnas.org/content/113/4/E440.abstract
“Out Of Africa” Bottleneck Is What Really Matters For Mutations: https://www.gnxp.com/WordPress/2017/04/26/out-of-africa-bottleneck-is-what-really-matters-for-mutations/
But there is also a lot of archaeological and some ancient genetic DNA now that indicates that the vast majority of non-African ancestry began to expand rapidly around 50-60,000 years ago. This is tens of thousands of years after the lowest value given above. Therefore, again we have to make recourse to a long period of separation before the expansion. This is not implausible on the face of it, but we could do something else: just assume there’s an artifact with their methods and the inferred date of divergence is too old. That would solve many of the issues.

I really don’t know if the above quibbles have any ramification for the site frequency spectrum of deleterious mutations. My own hunch is that no, it doesn’t impact the qualitative results at all.

Figure 3 clearly shows that Europeans are enriched for weak and moderately deleterious mutations (the last category produces weird results, and I wish they’d talked about this more, but they observe that strong deleterious mutations have issues getting detected). Ne is just the effective population size and s is the selection coefficient (bigger number, stronger selection).

Too Much Diversity: https://westhunt.wordpress.com/2012/11/30/too-much-diversity/
There’s a new paper out in Nature, by Wenqing Fu and many other people, about the recent origin of most variants in protein-coding genes. They conclude that most are less than 5-10,000 year old – younger in Europeans than in Africans. This is a natural consequence of the shape of human demographic history – there was a huge population increase with the advent of agriculture, and more people meant more mutations. That agricultural expansion happened somewhat earlier in the Middle East and Europe than in Africa.

...

A very few mutations are beneficial, some are neutral and many are deleterious, although the degree of harm inflicted varies widely. So the population expansion also increased the number of bad mutations – but unless selection also relaxed, it would not have changed the per-capita number of deleterious mutations, or the distribution of their effects (what fraction had large, medium, or small effects on fitness). It increased the diversity of deleterious mutations – they are more motley, not more common. The article never talks about that per-capita number, or, if it did , I was unable to winkle it out. It talks about ages and numbers of mutations – but not the mean number, in either of the two populations studied (European Americans and African Americans) . I think it would been a lot clearer, confused fewer reporters, if it had made that distinction. On the other hand, depending on the facts on the ground, talking about mutational load might be a grant-killer. There was a paper earlier this year (with many of the same authors) that used about half of the same data and did mention per-capita numbers. I’ve discussed it.

...

The paper says that there may be an excess of weakly deleterious mutations in Europeans due to bottlenecks back in the Ice Age. The idea works like this: selection is less efficient in small populations. Deleterious mutations with an effect s < 1/Ne drift freely and are not efficiently removed by selection. This effect takes on the order of Ne generations – so a population reduced to an effective size of of 10,000 for 10,000 generations ( ~250,000 years) would accumulate a large-than-usual number of deleterious mutations of effect size ~10-4. Lohmueller et al wrote about this back in 2008: the scenario they used had a European ancestral bottleneck 200,000 years long, which is A. what you need to make this scenario work and B. impossible, since it’s way before anatomically modern humans left Africa. Back to the drawing board.

disease alleles:
Ascertainment bias can create the illusion of genetic health disparities: https://www.biorxiv.org/content/early/2017/09/28/195768
study  genetics  regularizer  genetic-load  sapiens  europe  africa  comparison  world  recent-selection  org:nat  pop-structure  null-result  pop-diff  multi  evolution  roots  gnxp  scitariat  commentary  summary  migration  gene-drift  long-short-run  bio  preprint  🌞  debate  hmm  idk  disease  genomics  bioinformatics  spreading  west-hunter  antiquity  eden 
january 2017 by nhaliday
Information Processing: Directional dominance on stature and cognition
inbreeding depression in humans

After exclusion of outliers, these effect sizes translate into a reduction of 1.2 cm in height and 137 ml in FEV1 for the offspring of first cousins, and into a decrease of 0.3 s.d. in g and 10 months’ less educational attainment.
hsu  study  summary  iq  kinship  genetic-load  scitariat  embodied  biodet  behavioral-gen 
december 2016 by nhaliday
What’s the catch? | West Hunter
Neanderthals and the Wrath of Khan

if someone were to try to create a Neanderthal a few years from now, starting with ancient DNA, they’d have to have worry a lot about data errors, because such errors would translate into mutations, which might be harmful or even lethal. Assume that we have figured out how to get the gene expression right, have all the proper methylation etc: we have modern humans as a template and you know there isn’t that much difference.

They might try consensus averaging – take three high-quality Neanderthal genomes and make your synthetic genome by majority rule: we ignore a nucleotide change in one genome if it’s not there in the other two. ‘tell me three times’, a simple form of error-correcting code.

But doing this would cause a problem. Can you see what the problem is?
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november 2016 by nhaliday
Talkin’ ’bout their generations | West Hunter
According to the Decode results, mothers contribute 15 mutations, regardless of age, while men contribute 25 + 2*(g-20) mutations, when g is the average paternal age. As I pointed out earlier, if g is the same in both sexes, the average number of mutations is just 2g, which makes for 2 mutations per calendar year. I’ve been checking out average maternal age: it doesn’t vary much. The lowest I’ve seen was 26, the highest 30, so 28 is a reasonable number. So far, in the data we’ve gathered, the population with the highest paternal age was in Gambia, with an average paternal age of 47. If we assume that the average maternal age is 28 (which look about right from the graph: I haven’t digitized it yet) then the average kid would receive 94 new mutations (15 maternal, 79 paternal). With an average generation length of 37.5 years (the average of 28 and 47), that makes for 2.5 mutations per calendar year: about 15% higher than you would see in most populations, where the gap between average maternal and paternal age is not nearly as large.

A Gambia-sized gap would result in a noticeably higher rate of neutral genetic divergence. If it had existed long enough you might be able to notice it, but I think there’s a better chance of seeing this effect in Australian Aborigines, who had high average paternal age and might have had it for a long time. Other than the Australians, I would guess that all the old-dad societies are relatively recent.

The higher mutational load is not just a consequence of the higher per-year mutation rate in these old-dad societies – since generations are longer, there is less selection per calendar year (considering that most selection acts early in life). The number of mutations per generation is probably the most important number. I found some numbers for Polar Eskimos, hunter-gatherers (they gather snow) in a tough environment: average maternal age was 27, average paternal age was 32, for an average generation length of 29.5. They’d have 64 mutations a generation: the per-generation rate in Gambia is 47% higher.

There are also qualitative differences in selection: selection is weaker in childhood and stronger in midlife in an old-dad society, as Henry pointed out. So that situation should select for longer life, except that’s hard to manage in the presence of higher-than-usual genetic load.

https://westhunt.wordpress.com/2012/10/19/base-substitutions-and-deletions/
According to Jim Crow”s 2006 article, base substitutions are mostly (overwhelmingly) from males and increase with paternal age, but small deletions are contributed about equally by males and females, with no noticeable age effect. Probably the deletions happen during meiosis.

So, with a huge gene like those involved in Duchenne’s muscular dystrophy or neurofibromatosis I, which have many exons (79 for dystrophin), many of the mutations are caused by deletions. The paternal age effect is weaker for those syndromes (since less than half of the causal mutations are base substitutions)

https://westhunt.wordpress.com/2012/08/26/gerontocratic-polygyny/
https://westhunt.wordpress.com/2012/09/05/obvious-yessss-it-was-obvious/
https://westhunt.wordpress.com/2012/08/22/paternal-age/
https://westhunt.wordpress.com/2012/09/17/gambia/
https://westhunt.wordpress.com/2012/09/16/paternal-age-and-the-force-of-mortality/
No surprises here save one. While selection for survival should extend male lifespans by 10 to 20 years in the case of old fathers, selection for survival before the age of reproduction is much weaker in the the case of older fathers. A prediction is that adolescent and young male death rates should be higher in old father societies because selection is weaker. I never realized that.

Hamilton’s theory does not describe human life history very well, as Rogers shows in his Figure 16.1 and discusses in the text. Human female fertility ceases long before the theory predicts that it should and humans live much longer. The reconciliation certainly has to do with kin selection or indirect selection. For example Kris Hawkes pushes the “grandmother hypothesis” according to which females cease reproduction and instead work for their daughters’ children. If she is right this grandmother effect selected for the prolonged human lifespan, and the long lifespan of males is a side-effect of selection for long life in females.
west-hunter  objektbuch  genetics  genetic-load  developmental  paternal-age  epidemiology  science-anxiety  scitariat  multi  social-structure  life-history  mutation  🌞  effect-size  data  ideas  speculation  methodology  gender  gender-diff  sex  africa  recent-selection  pop-diff  kinship  selection  population-genetics  electromag  longevity  aging  iq  intelligence  neuro  eden  explanans  age-generation 
november 2016 by nhaliday
Degenerate Neanderthals | West Hunter
Both papers talk about the likely genetic burden that Eurasians picked up from that Neanderthal admixture. Since East Asians have a somewhat higher level of Neanderthal admixture than people in Europe or the Middle East (~20% more) then they must have even more toxic Neanderthal genes, and Africans the least. This echoes earlier papers that have argued that population history (out-of-Africa bottleneck, Neanderthal admixture, etc) must have increased genetic load in Eurasians.
Evidently extra genetic load has anti-intuitive effects.

interesting: https://westhunt.wordpress.com/2015/11/03/degenerate-neanderthals/#comment-73074
http://onlinelibrary.wiley.com/doi/10.1111/j.0014-3820.2000.tb00693.x/abstract

COMPENSATING FOR OUR LOAD OF MUTATIONS: FREEZING THE MELTDOWN OF SMALL POPULATIONS

The model allows us to investigate compensatory mutations, which restore fitness losses incurred by other mutations, in a context-dependent manner. We have conducted a moment analysis of the model, supplemented by the numerical results of computer simulations. The mean reduction of fitness (i.e., expected load) scaled to one is approximately n/(n + 2Ne), where Ne is the effective population size. The reciprocal relationship between the load and Ne implies that the fixation of deleterious mutations is unlikely to cause extinction when there is a broad scope for compensatory mutations, except in very small populations. Furthermore, the dependence of load on n implies that pleiotropy plays a large role in determining the extinction risk of small populations.
west-hunter  sapiens  genetics  genetic-load  archaics  speculation  methodology  competition  population-genetics  gene-flow  europe  critique  evolution  mutation  pop-structure  multi  study  links  commentary  discussion  context  dimensionality  scitariat  stylized-facts  poast  gene-drift  population  magnitude  street-fighting  nibble  aphorism  pop-diff  africa  antiquity  comparison  troll  lol  stereotypes  alien-character  speaking 
november 2016 by nhaliday
The Day Before Forever | West Hunter
Yesterday, I was discussing the possibilities concerning slowing, or reversing aging – why it’s obviously possible, although likely a hard engineering problem. Why partial successes would be valuable, why making use of the evolutionary theory of senescence should help, why we should look at whales and porcupines as well as Jeanne Calment, etc., etc. I talked a long time – it’s a subject that has interested me for many years.

But there’s one big question: why are the powers that be utterly uninterested ?

https://www.facebook.com/ISIInc/videos/vb.267919097102/641005449680861/?type=2&theater
The Intercollegiate Studies Institute and the Abagail Adams Institute host a debate between Peter Thiel and William Hurlbut. Resolved: Technology Should Treat Death as an Enemy

https://westhunt.wordpress.com/2017/07/03/the-best-things-in-life-are-cheap-today/
What if you could buy an extra year of youth for a million bucks (real cost). Clearly this country ( or any country) can’t afford that for everyone. Some people could: and I think it would stick in many people’s craw. Even worse if they do it by harvesting the pineal glands of children and using them to manufacture a waxy nodule that forfends age.

This is something like the days of old, pre-industrial times. Back then, the expensive, effective life-extender was food in a famine year.

https://westhunt.wordpress.com/2017/04/11/the-big-picture/
Once upon a time, I wrote a long spiel on life extension – before it was cool, apparently. I sent it off to an interested friend [a science fiction editor] who was at that time collaborating on a book with a certain politician. That politician – Speaker of the House, but that could be anyone of thousands of guys, right? – ran into my spiel and read it. His immediate reaction was that greatly extending the healthy human life span would be horrible – it would bankrupt Social Security ! Nice to know that guys running the show always have the big picture in mind.

Reminds me of a sf story [Trouble with Lichens] in which something of that sort is invented and denounced by the British trade unions, as a plot to keep them working forever & never retire.

https://westhunt.wordpress.com/2015/04/16/he-still-has-that-hair/
He’s got the argument backward: sure, natural selection has not favored perfect repair, so says the evolutionary theory of of senescence. If it had, then we could perhaps conclude that perfect repair was very hard to achieve, since we don’t see it, at least not in complex animals.* But since it was not favored, since natural selection never even tried, it may not be that difficult.

Any cost-free longevity gene that made you live to be 120 would have had a small payoff, since various hazards were fairly likely to get you by then anyway… And even if it would have been favored, a similar gene that cost a nickel would not have been. Yet we can afford a nickel.

There are useful natural examples: we don’t have to start from scratch. Bowhead whales live over 200 years: I’m not too proud to learn from them.

Lastly , this would take a lot of work. So what?

*Although we can invent things that evolution can’t – we don’t insist that all the intermediate stages be viable.

https://westhunt.wordpress.com/2013/12/09/aging/
https://westhunt.wordpress.com/2014/09/22/suspicious-minds/

doesn't think much of Aubrey de Gray: https://westhunt.wordpress.com/2013/07/21/of-mice-and-men/#comment-15832
I wouldn’t rely on Aubrey de Gray.

It might be easier to fix if we invested more than a millionth of a percent of GNP on longevity research. It’s doable, but hardly anyone is interested. I doubt if most people, including most MDs and biologists, even know that it’s theoretically possible.

I suppose I should do something about it. Some of our recent work ( Henry and me) suggests that people of sub-Saharan African descent might offer some clues – their funny pattern of high paternal age probably causes the late-life mortality crossover, it couldn’t hurt to know the mechanisms involved.

Make Room! Make Room!: https://westhunt.wordpress.com/2015/06/24/make-room-make-room/
There is a recent article in Phys Rev Letters (“Programed Death is Favored by Natural Selection in Spatial Systems”) arguing that aging is an adaptation – natural selection has favored mechanisms that get rid of useless old farts. I can think of other people that have argued for this – some pretty smart cookies (August Weismann, for example, although he later abandoned the idea) and at the other end of the spectrum utter loons like Martin Blaser.

...

There might could be mutations that significantly extended lifespan but had consequences that were bad for fitness, at least in past environments – but that isn’t too likely if mutational accumulation and antagonistic pleiotropy are the key drivers of senescence in humans. As I said, we’ve never seen any.

more on Martin Blaser:
https://westhunt.wordpress.com/2013/01/22/nasty-brutish-but-not-that-short/#comment-7514
This is off topic, but I just read Germs Are Us and was struck by the quote from Martin Blaser ““[causing nothing but harm] isn’t how evolution works” […] “H. pylori is an ancestral component of humanity.”
That seems to be the assumption that the inevitable trend is toward symbiosis that I recall from Ewald’s “Plague Time”. My recollection is that it’s false if the pathogen can easily jump to another host. The bulk of the New Yorker article reminded me of Seth Roberts.

I have corresponded at length with Blaser. He’s a damn fool, not just on this. Speaking of, would there be general interest in listing all the damn fools in public life? Of course making the short list would be easier.

https://westhunt.wordpress.com/2013/01/18/dirty-old-men/#comment-64117
I have corresponded at length with Blaser. He’s a damn fool, not just on this. Speaking of, would there be general interest in listing all the damn fools in public life? Of course making the short list would be easier.
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november 2016 by nhaliday
The Third Sex | West Hunter
- eusociality and humans
- chromosome morphs
- green-beards and asabiya
- MHC/HLA and mating
- white-throated sparrows

Strategies: https://westhunt.wordpress.com/2017/12/27/strategies/
There is a qualitative difference between being XY and X0 (Turner’s syndrome). Being XY, a guy, is the physical embodiment of an evolutionary strategy: a certain genetic pattern that has a way of making more copies of itself. It’s a complex strategy, but that’s what it is. X0 people are sterile: they don’t generate more X0 individuals. Not every XY individual succeeds in reproducing, any more than every maple seed starts a new maple tree – but on average, it works. An X0 individual is the result of noise, errors in meiosis: Turner’s syndrome isn’t a strategy. In the same way, someone with Down’s syndrome isn’t Nature’s way of producing more people with Down’s syndrome.

Parenthetically, being a guy that tries to reproduce is a strategy. Actually reproducing is a successful outcome of that strategy. Similarly, being an alpha dude in a polygynous species like elephant seals is not a strategy: trying to be an alpha dude is the strategy. I see people confuse those two things all the time.

...

Natural selection tends to make physical embodiments of a successful reproductive strategy common. So stuff like Down’s syndrome, Turner’s syndrome, androgen insensitivity, etc, are all rare. Successful evolutionary strategies usually involve actually getting things done: so there is a tendency for natural selection to develop and optimize various useful abilities, like walking and talking and thinking. All part of the strategy. Many non-strategies [like Downs or Fragile X] mess up those abilities

...

So, is sex a spectrum in humans? No: obviously not. Two basic strategies, plus errors.

Why would a geneticist be unable to make the distinction between an evolutionary strategy and an error of development (i.e. caused by replication errors of pathogens)? Well, the average geneticist doesn’t know much evolutionary biology. And being embedded in a university, the current replacement for old-fashioned booby hatches, he’s subject to pressures that reward him for saying stupid things. and of course some people are pre-adapted to saying stupid things.

https://westhunt.wordpress.com/2017/12/27/strategies/#comment-98964
My whole point was that you can explain the qualitative difference without being in any way teleological. You’d do better to think about positive igon-values than Aristotle.
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october 2016 by nhaliday
The impact of recent population history on the deleterious mutation load in humans and close evolutionary relatives | bioRxiv
Over the past decade, there has been both great interest and confusion about whether recent demographic events - notably the Out-of-Africa-bottleneck and recent population growth - have led to differences in mutation load among human populations. The confusion can be traced to the use of different summary statistics to measure load, which lead to apparently conflicting results. We argue, however, that when statistics more directly related to load are used, the results of different studies and data sets consistently reveal _little or no difference_ in the load of non-synonymous mutations among human populations.
sapiens  genetics  study  preprint  race  genetic-load  bio  pop-structure  homo-hetero 
september 2016 by nhaliday

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