Distribution of fitness effects of mutations?

Haven’t had a time to check this paper out, but looks real interesting, Assessing the Evolutionary Impact of Amino Acid Mutations in the Human Genome:

Although mutations are known to cause varying degrees of harmful effects, it is difficult to quantify the distribution that best describes the variation of fitness effects of these mutations. Here we present a new method for inferring this distribution and inferring population history using Single Nucleotide Polymorphism (SNP) data from human populations. Using 47,576 SNPs discovered in 11,404 genes from sequencing 35 individuals (20 European Americans and 15 African Americans), we find evidence of an ancient population expansion in the sample with African ancestry and a relatively recent bottleneck in the sample with European ancestry. In both populations, the patterns of variation are consistent with a leptokurtic distribution of selection coefficients (e.g., gamma or log-normal) peaked near neutrality. Specifically, we predict 27-29% of amino acid changing (nonsynonymous) mutations are neutral or nearly neutral, 30-42% are moderately deleterious, and nearly all the remainder are highly deleterious or lethal. Furthermore, we infer that 10-20% of amino acid differences between humans and chimpanzees were fixed by positive selection, with the remainder of differences being neutral or nearly neutral.

Leptokurtosis describes a more acute peak around the mean.

French more fecund than the Irish?

Walker’s World: French births soar:

The second development to note is that INED, France’s National Institute of Demographic Studies, has done some detailed research and concluded that France’s immigrant population is responsible for only 5 percent of the rise in the birthrate and that France’s population would be rising anyway even without the immigrant population.

In fact in France, like everywhere else in Europe, the birthrate among immigrant mothers drops quickly toward the local norm in less than two generations. The measure most commonly used in international statistics is the Total Fertility Rate, which seeks to measure the number of children born to the average woman in her fertile years…

In France, the TFR has risen from 1.66 in 1993 to 2.0 in 2003 and 2.1 last year. If maintained, that means the population of France will rise from 60.7 million today to 70 million sometime before 2050.

The birthrates of Muslim women in Europe have been falling significantly for some time. In the Netherlands, for example, the TFR among Dutch-born women rose between 1990 and 2005 from 1.6 to 1.7. In the same period for Moroccan-born women in Holland it fell from 4.9 to 2.9, and for Turkish-born women in Holland from 3.2 to 1.9.

In Austria, the TFR of Muslim women fell from 3.1 to 2.3 from 1981 to 2001. In 1970 Turkish-born women in Germany had on average two children more than German-born women. By 1996 the difference had fallen to one child and has now dropped to 0.5….

A few points. First, even if there is convergence differentials still do matter. One thing I noted when surveying data on Mormon fertility is that though it has converged with non-Mormon fertility, the “floor” still usually remains higher than that of local non-Mormons. I’m not worried about a Mormon future of course because it is also a religion with a relatively high defection rate, but long term persistence of small differences do matter. Second, projecting to the year 2100 as many do today is very problematic. In the late 19th century some bureaucrats in the Ottoman government were relieved as the Christian Balkan provinces fell away through independence or assimilation into the Austro-Hungarian monarchy. The reason being the fact that Christians had higher fertility than Muslims; something most Muslims and Christians today would find a very peculiar worry. In there is a reference to a racial triumphalist demographer writing in 1900 about the “fact” that in the year 2000 there will be 1.5 billion whites and only 400 million Han Chinese. Finally, variance matters. Note:

Germany is something of an oddity in this. In most countries with low fertility, young women have their first child late, and stop at one. In Germany, women with children often have two or three. But many have none at all.

Italy and Germany might both have low expectations in regards to the number of children a woman may have in her lifetime, but the shape of the distribution may matter a great deal if fertility is heritable to any extent (straight out of here). Heritability need not be physiological; rather, it might be cultural and psychological propensities transmitted to the next generation. But if the data above hold one might expect German fertility to bounce back faster than Italian because a subset of the German population exhibit pro-natalist sentiments.

(H/T Talk Islam)

First Greenlanders left no descendents?

Here’s another example of how genetic methods can shed light on archaeological questions, Paleo-Eskimo mtDNA Genome Reveals Matrilineal Discontinuity in Greenland:

The Paleo-Eskimo Saqqaq and Independence I cultures, documented from archaeological remains in Northern Canada and Greenland, represent the earliest human expansion into the New World’s northern extremes. However, their origin and genetic relationship to later cultures is unknown. We sequenced a mitochondrial genome from a Paleo-Eskimo human, using 3400- to 4500-year-old frozen hair excavated from an early Greenlandic Saqqaq settlement. The sample is distinct from modern Native Americans and Neo-Eskimos, falling within haplogroup D2a1, a group previously observed among modern Aleuts and Siberian Sireniki Yuit. This suggests that the earliest migrants into the New World’s northern extremes derived from populations in the Bering Sea area, and were neither directly related to Native Americans nor the later Neo-Eskimos that replaced them.

New Scientist has a popular press profile of the research & findings. Remember last year when it was confirmed that Polynesians had to have been visiting the coast of South America because of the phylogeny of chicken DNA extracted from subfossils? Though there have always been hints, I think this suggests greater complexities to our picture of the pre-Columbian world. Do note that this is one mitochondrial DNA lineage. It shows lack of perfect continuity, but does not entail total replacement….
Update: “Polynesian” chickens might not be in the bag yet. See comment.

Genetic orthodoxy?

John Hawks, in a post on scientists who dispute the acceleration hypothesis (acceleration deniers?), makes reference to “the Stanford school of genetic orthodoxy”. So what is this?

Essentially, he’s referring to the current paradigm (I’m as much of a fan of hyperbole as anyone else, but paradigm is clearly the more appropriate word here) in the field of population genetics about the peopling of the world. The story goes like this: a small set of individuals from an ancestral population in Africa moved somewhere in the Middle East, and grew. Then from there, a small set of individuals moved nearby in each direction and settled. Ditto for those populations, and so on. These “serial bottlenecks” kept occurring until the entire world was populated, replacing the individuals that were there before them.

The observation that solidified this paradigm comes from this paper, which showed an impressive negative correlation between distance from East Africa and genetic diversity, consistent with each population containing a subset of the diversity of the populations it came from. Since then, that sort of approach has been used in a number of similar applications, including this nice one on the peopling of the Americas.

Further support for this paradigm comes from more recent work modeling human demography–it’s simply not true that this out-of-Africa hypothesis is enforced like an orthodoxy. See, for example this paper entitled “Statistical evaluation of alternative models of human evolution” (lest you think that alternative models of human evolution aren’t being evaluated), which concludes for a single origin of humans in Africa. This doesn’t test the “serial bottleneck” model, but does address the multiregional hypothesis, which I think is the major point for Hawks. Or consider a more recent paper, which attempts (with moderate success) to infer the colonization history of the world. The results favor out-of-Africa, as well as serial bottlenecks (though theses bottleneck, it must be noted, were essentially built into their model).

Now, new data may alter some of these models somewhat–David Reich and other claim here (in a News and Views article) that they see evidence for multiple waves of migration from Africa in PCA analysis, though it remains to be seen how those results hold up.

I’m not sure what Hawks thinks of these papers–for all I know, they’re making the multiregional hypothesis into a statistical straw man that is easily demolished, but the point remains that the consolidation of these observations into a paradigm is not entirely without reason. The statistical methods and genetic data are available to challenge it, and skeptics (I know many) are more than welcome to try their hand.

Congratulations to Jonathan Pritchard

Innovation in genetic variation research garners Jonathan Pritchard HHMI investigator appointment at University. HHMI = Howard Hughes Medical Institute. So when are we going to see him in Chicago Magazine? In any case:

In a 2006 paper, Pritchard and his colleagues described the identification of several hundred DNA regions in various human populations that show signals of selection. Included within those regions are genes that influence reproduction, olfaction and degradation of environmental toxins, skin pigmentation and skeletal development.

Using more extensive data that have recently become available, his group has been examining the relative roles of chance (which can lead to changes in the gene pool known as genetic drift) and selection in favoring these genes. “Selection may be a weaker force than we thought,” he said. “It seems to be a combination of drift and selection acting together.”

Things that make you go hmmmmm….

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Measuring the age of white supremacy

vickers.jpgI’m getting into an exchange with Luis below about the rise of European domination. Unfortunately with historical questions I can’t “prove” my case as in mathematics, nor can I cite an empirical result that is extremely generalizable as in much of the natural sciences. I’m trying to describe a distribution of facts over time and space, and I can’t really make my own position clear without plugging into Luis’ mind all my priors (the inverse might apply from Luis’ perspective). That takes time and is basically impossible in blog-format, though I’ve had better success I think in face-to-face conversation because the per unit density of data which can be transmitted quickly. So, two quick points.

Read More

Short Guide to the Human Genome

Just got a copy of , put out by Cold Spring Harbor Laboratory. It’s a fun little review; appropriate for browsing during your “in-between” time. As the title emphasizes this guide is characterized by extreme brevity, under 200 pages. Nevertheless it attempts a survey of the major results which have come to light over the past decade in human genomics. This isn’t really a primer, it assumes you know what UTR stands for and why spliceosomes are important. In other words, return on investment is probably only there if you are reasonably familiar with the basics of molecular genetic terminology so that you don’t always have to keep running for references. The guide is divided into broad thematic sections, for example, “RNA” or “comparative genomics.” Within these chapters are compact sections with headings in the form of aquestion. After some short introductory exposition (usually a sentence or two), you are presented with a table or chart which summarizes the main finding, followed by further clarifying exposition. Methods and data sources are always appended, and quite frequently you’ll also find a citation to papers which cover the topic being addressed. The author notes that this book was written as an extended response to the most common questions asked about the human genome, so don’t be surprised if you stumble upon something you might have wondered about but never followed up.

Positive selection on EDAR, why East Asians & Native Americans have thick hair

Positive Selection in East Asians for an EDAR Allele that Enhances NF-κB Activation:

Genome-wide scans for positive selection in humans provide a promising approach to establish links between genetic variants and adaptive phenotypes. From this approach, lists of hundreds of candidate genomic regions for positive selection have been assembled. These candidate regions are expected to contain variants that contribute to adaptive phenotypes, but few of these regions have been associated with phenotypic effects. Here we present evidence that a derived nonsynonymous substitution (370A) in EDAR, a gene involved in ectodermal development, was driven to high frequency in East Asia by positive selection prior to 10,000 years ago. With an in vitro transfection assay, we demonstrate that 370A enhances NF-κB activity. Our results suggest that 370A is a positively selected functional genetic variant that underlies an adaptive human phenotype.

We’ve blogged about EDAR before; Could it be hair form?, EDAR controls hair thickness and EDAR and hair thickness. The story here is simple, before the populations ancestral to the Native Americans had left eastern Asia a mutation on the EDAR gene swept nearly to fixation among these populations. The derived SNP in particular is correlated with the thicker hair typical of East Asians and Native Americans. In other populations (Europeans, Africans, West and South Asians as well as Papuans and Melanesians) the SNP is in an ancestral state. The main twist in this study is that they used a molecular genetic technique to show that this derived state seems to upregulate the activity of NF-κB transcription factor.

For the record, I’m really skeptical that this selective sweep occurred because the human populations of late Ice Age eastern Asia developed a really strong attraction to thick luxuriant hair with full body. The paper is Open Access, read the whole thing. Since the most interesting figure is either too small or too large, I’ve resized it appropriately and placed it below the fold.