抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

https://cdr.lib.unc.edu/downloads/v692t8920

A global reference for human genetic variation.

Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

Human biochemical genetics

The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10(-8) per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research.

http://dash.harvard.edu/bitstream/handle/1/5339502/Durbin_MapHuman.pdf?sequence=1

A Map of Human Genome Variation From Population-Scale Sequencing

All else being equal, the ratio of genetic diversity levels on X and autosomes at selectively neutral sites should mirror the ratio of their numbers in the population and thus equal ¾. Because X chromosomes spend twice as many generations in females as in males, however, the ratio of diversity levels is also affected by sex differences in life history. The effects of life history on diversity levels, notably those of sex-specific age structures and reproductive variances, have been studied for decades, yet existing theory relies on many parameters that are difficult to measure and lacks generality in ways that limit their applicability. We derive general yet simple expressions for these effects and show that life history effects on X-to-autosome (X:A) ratios of diversity levels depend only on sex-ratios of mutation rates, generation times, and reproductive variances. These results reveal that changing the sex-ratio of generation times has opposite effects on X:A ratios of polymorphism and divergence. They also explain how sex-specific life histories modulate the response of X:A polymorphism ratios to changes in population size. More generally, they clarify that sex-specific life history—generation times in particular—should have a marked effect on X:A polymorphism ratios in many taxa and enable the investigation of these effects. Significance Statement Understanding the determinants of neutral diversity patterns on autosomes and sex chromosomes provides a bedrock for our interpretation of population genetic data. Sex-specific age-structure and variation in reproductive success have long been thought to affect neutral diversity, but theoretical descriptions of these effects were complicated and/or lacked in generality, stymying attempts to relate diversity patterns of species with their life history. We derive general yet simple expressions for these effects, which clarify how they impact neutral diversity and should enable studies of relative diversity levels on the autosomes and sex chromosomes in many taxa.

https://www.biorxiv.org/content/biorxiv/early/2019/09/10/206862.full.pdf

Life history effects on neutral diversity levels of autosomes and sex chromosomes

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. Theory helps to understand why no such differences are seen, as well as to predict in what settings they are to be expected. In particular, as predicted by modeling, there is evidence for changes in the load of recessive loss of function mutations in founder and inbred human populations. Also as predicted, eastern subspecies of gorilla, Neanderthals and Denisovans, who are thought to have undergone reductions in population sizes that exceed the human Out-of-Africa bottleneck in duration and severity, show evidence for increased load of non-synonymous mutations (relative to western subspecies of gorillas and modern humans, respectively). A coherent picture is thus starting to emerge about the effects of demographic history on the mutation load in populations of humans and close evolutionary relatives.

/pdf/the-impact-of-recent-population-history-on-the-deleterious-l5xnpeui3n.pdf

The impact of recent population history on the deleterious mutation load in humans and close evolutionary relatives

Mutation rates and spectra differ among human populations. Here, we examine whether this variation could be explained by evolution at mutation modifiers. To this end, we consider genetic modifier sites at which mutations, "mutator alleles", increase genome-wide mutation rates and model their evolution under purifying selection due to the additional deleterious mutations that they cause, genetic drift, and demographic processes. We solve the model analytically for a constant population size and characterize how evolution at modifier sites impacts variation in mutation rates within and among populations. We then use simulations to study the effects of modifier sites under a plausible demographic model for Africans and Europeans. When comparing populations that evolve independently, weakly selected modifier sites (2Nes {approx} 1), which evolve slowly, contribute the most to variation in mutation rates. In contrast, when populations recently split from a common ancestral population, strongly selected modifier sites (2Nes >> 1), which evolve rapidly, contribute the most to variation between them. Moreover, a modest number of modifier sites (e.g., 10 per mutation type in the standard classification into 96 types) subject to moderate to strong selection (2Nes > 1) could account for the variation in mutation rates observed among human populations. If such modifier sites indeed underlie differences among populations, they should also cause variation in mutation rates within populations and their effects should be detectable in pedigree studies.

/pdf/the-impact-of-genetic-modifiers-on-variation-in-germline-1tajd154b2.pdf

The impact of genetic modifiers on variation in germline mutation rates within and among human populations

In many species, meiotic recombination events tend to occur in narrow intervals of the genome, known as hotspots. In humans and mice, double strand break (DSB) hotspot locations are determined by the DNA-binding specificity of the zinc finger array of the PRDM9 protein, which is rapidly evolving at residues in contact with DNA. Previous models explained this rapid evolution in terms of the need to restore PRDM9 binding sites lost to gene conversion over time, under the assumption that more PRDM9 binding always leads to more DSBs. In recent experimental work, however, it has become apparent that PRDM9 binding on both homologs facilitates DSB repair, and moreover that, in the absence of enough symmetric binding, meiosis no longer progresses reliably. We therefore consider the possibility that the benefit of PRDM9 stems from its role in coupling DSB formation and efficient repair. To this end, we model the evolution of PRDM9 from first principles: from its binding dynamics to the population processes that govern the evolution of the zinc finger array and its binding sites in the genome. As we show, the loss of a small number of strong binding sites leads to the use of a greater number of weaker ones, resulting in a sharp reduction in symmetric binding and favoring new PRDM9 alleles that restore the use of a smaller set of strong binding sites. This decrease in PRDM9 binding symmetry and in its ability to promote DSB repair drive the rapid zinc finger turnover. These results imply that the advantage of new PRDM9 alleles is in limiting the number of binding sites used effectively, rather than in increasing net PRDM9 binding, as previously believed. By extension, our model suggests that the evolutionary advantage of hotspots may have been to increase the efficiency of DSB repair and/or homolog pairing.

/pdf/down-the-penrose-stairs-how-selection-for-fewer-14hxkc02.pdf

Down the Penrose stairs: How selection for fewer recombination hotspots maintains their existence

Sub-populations of cooperators and defectors inhabit sites on a lattice. The interactions among the individuals at a site, in the form of a prisoners-dilemma (PD) game, determine their fitnesses. The PD pay-off parameters are chosen so that cooperators are able to maintain a homogeneous population, while defectors are not. Individuals mutate to become the other type and migrate to a neighboring site with low probabilities. Both density dependent and density independent versions of the model are studied. The dynamics of the model can be understood by considering the life-cycle of a population at a site. This life-cycle starts with one cooperator establishing a population. During this life-cycle new cooperator populations are founded by single cooperators that migrate out to empty neighboring sites. The system can reach a steady state where cooperation prevails if the global ``birth'' rate of populations is equal to the rate of their ``death.'' This steady state is dynamic in nature---cooperation persists although every single population of cooperators dies out. These dynamics enable the persistence of cooperation in a large section of the model's parameter space. Submitted to Journal of Theoretical Biology

Guy Sella

Papers

Life history effects on neutral diversity levels of autosomes and sex chromosomes

The impact of recent population history on the deleterious mutation load in humans and close evolutionary relatives

The impact of genetic modifiers on variation in germline mutation rates within and among human populations

Down the Penrose stairs: How selection for fewer recombination hotspots maintains their existence

On the Dynamic Persistence of Cooperation: How Lower Fitness Induces Higher Survivability