Molly Przeworski

Molecular evolution of FOXP2, a gene involved in speech and language.

Language is a uniquely human trait likely to have been a prerequisite for the development of human culture. The ability to develop articulate speech relies on capabilities, such as fine control of the larynx and mouth, that are absent in chimpanzees and other great apes. FOXP2 is the first gene relevant to the human ability to develop language. A point mutation in FOXP2 co-segregates with a disorder in a family in which half of the members have severe articulation difficulties accompanied by linguistic and grammatical impairment. This gene is disrupted by translocation in an unrelated individual who has a similar disorder. Thus, two functional copies of FOXP2 seem to be required for acquisition of normal spoken language. We sequenced the complementary DNAs that encode the FOXP2 protein in the chimpanzee, gorilla, orang-utan, rhesus macaque and mouse, and compared them with the human cDNA. We also investigated intraspecific variation of the human FOXP2 gene. Here we show that human FOXP2 contains changes in amino-acid coding and a pattern of nucleotide polymorphism, which strongly suggest that this gene has been the target of selection during recent human evolution.

Linkage Disequilibrium in Humans: Models and Data

In this review, we describe recent empirical and theoretical work on the extent of linkage disequilibrium (LD) in the human genome, comparing the predictions of simple population-genetic models to available data. Several studies report significant LD over distances longer than those predicted by standard models, whereas some data from short, intergenic regions show less LD than would be expected. The apparent discrepancies between theory and data present a challenge-both to modelers and to human geneticists-to identify which important features are missing from our understanding of the biological processes that give rise to LD. Salient features may include demographic complications such as recent admixture, as well as genetic factors such as local variation in recombination rates, gene conversion, and the potential segregation of inversions. We also outline some implications that the emerging patterns of LD have for association-mapping strategies. In particular, we discuss what marker densities might be necessary for genomewide association scans.

PRDM9 is a Major Determinant of Meiotic Recombination Hotspots in humans and mice

Homing in on Hotspots The clustering of recombination in the genome, around locations known as hotspots, is associated with specific DNA motifs. Now, using a variety of techniques, three studies implicate a chromatin-modifying protein, the histone-methyltransferase PRDM9, as a major factor involved in human hotspots (see the Perspective by Cheung et al.). Parvanov et al. (p. 835, published online 31 December) mapped the locus in mice, and analyzed allelic variation in mice and humans, whereas Myers et al. (p. 876, published online 31 December) used a comparative analysis between human and chimpanzees to show that the recombination process leads to a self-destructive drive in which the very motifs that recruit hotspots are eliminated from our genome. Baudat et al. (p. 836, published online 31 December) took this analysis a step further to identify human allelic variants within Prdm9 that differed in the frequency at which they used hotspots. Furthermore, differential binding of this protein to different human alleles suggests that this protein interacts with specific DNA sequences. Thus, PDRM9 functions in the determination of recombination loci within the genome and may be a significant factor in the genomic differences between closely related species. A chromatin-modifying enzyme is implicated in the determination of recombination loci within the genome. Meiotic recombination events cluster into narrow segments of the genome, defined as hotspots. Here, we demonstrate that a major player for hotspot specification is the Prdm9 gene. First, two mouse strains that differ in hotspot usage are polymorphic for the zinc finger DNA binding array of PRDM9. Second, the human consensus PRDM9 allele is predicted to recognize the 13-mer motif enriched at human hotspots; this DNA binding specificity is verified by in vitro studies. Third, allelic variants of PRDM9 zinc fingers are significantly associated with variability in genome-wide hotspot usage among humans. Our results provide a molecular basis for the distribution of meiotic recombination in mammals, in which the binding of PRDM9 to specific DNA sequences targets the initiation of recombination at specific locations in the genome.

THE SIGNATURE OF POSITIVE SELECTION ON STANDING GENETIC VARIATION

Abstract Considerable interest is focused on the use of polymorphism data to identify regions of the genome that underlie recent adaptations. These searches are guided by a simple model of positive selection, in which a mutation is favored as soon as it arises. This assumption may not be realistic, as environmental changes and range expansions may lead previously neutral or deleterious alleles to become beneficial. We examine what effect this mode of selection has on patterns of variation at linked neutral sites by implementing a new coalescent model of positive directional selection on standing variation. In this model, a neutral allele arises and drifts in the population, then at frequency f becomes beneficial, and eventually reaches fixation. Depending on the value of f, this scenario can lead to a large variance in allele frequency spectra and in levels of linkage disequilibrium at linked, neutral sites. In particular, for intermediate f, the beneficial substitution often leads to a loss of rare alleles–a pattern that differs markedly from the signature of directional selection currently relied on by researchers. These findings highlight the importance of an accurate characterization of the effects of positive selection, if we are to reliably identify recent adaptations from polymorphism data.

Loss of Olfactory Receptor Genes Coincides with the Acquisition of Full Trichromatic Vision in Primates

Olfactory receptor (OR) genes constitute the molecular basis for the sense of smell and are encoded by the largest gene family in mammalian genomes. Previous studies suggested that the proportion of pseudogenes in the OR gene family is significantly larger in humans than in other apes and significantly larger in apes than in the mouse. To investigate the process of degeneration of the olfactory repertoire in primates, we estimated the proportion of OR pseudogenes in 19 primate species by surveying randomly chosen subsets of 100 OR genes from each species. We find that apes, Old World monkeys and one New World monkey, the howler monkey, have a significantly higher proportion of OR pseudogenes than do other New World monkeys or the lemur (a prosimian). Strikingly, the howler monkey is also the only New World monkey to possess full trichromatic vision, along with Old World monkeys and apes. Our findings suggest that the deterioration of the olfactory repertoire occurred concomitant with the acquisition of full trichromatic color vision in primates.

Classic selective sweeps were rare in recent human evolution

Much human genetic variation is likely due to purifying selection against deleterious mutations. Efforts to identify the genetic basis of human adaptations from polymorphism data have sought footprints of “classic selective sweeps” (in which a beneficial mutation arises and rapidly fixes in the population).Yet it remains unknown whether this form of natural selection was common in our evolution. We examined the evidence for classic sweeps in resequencing data from 179 human genomes. As expected under a recurrent-sweep model, we found that diversity levels decrease near exons and conserved noncoding regions. In contrast to expectation, however, the trough in diversity around human-specific amino acid substitutions is no more pronounced than around synonymous substitutions. Moreover, relative to the genome background, amino acid and putative regulatory sites are not significantly enriched in alleles that are highly differentiated between populations. These findings indicate that classic sweeps were not a dominant mode of human adaptation over the past ~250,000 years.

High-Resolution Mapping of Crossovers Reveals Extensive Variation in Fine-Scale Recombination Patterns Among Humans

Recombination plays a crucial role in meiosis, ensuring the proper segregation of chromosomes. Recent linkage disequilibrium (LD) and sperm-typing studies suggest that recombination rates vary tremendously across the human genome, with most events occurring in narrow “hotspots.” To examine variation in fine-scale recombination patterns among individuals, we used dense, genome-wide single-nucleotide polymorphism data collected in nuclear families to localize crossovers with high spatial resolution. This analysis revealed that overall recombination hotspot usage is similar in males and females, with individual hotspots often active in both sexes. Across the genome, roughly 60% of crossovers occurred in hotspots inferred from LD studies. Notably, however, we found extensive and heritable variation among both males and females in the proportion of crossovers occurring in these hotspots.

A neutral explanation for the correlation of diversity with recombination rates in humans.

One of the most striking findings to emerge from the study of genomic patterns of variation is that regions with lower recombination rates tend to have lower levels of intraspecific diversity but not of interspecies divergence. This uncoupling of variation within and between species has been widely interpreted as evidence that natural selection shapes patterns of genetic variability genomewide. We revisited the relationship between diversity, divergence, and recombination in humans, using data from closely related species and better estimates of recombination rates than previously available. We show that regions that experience less recombination have reduced divergence to chimpanzee and to baboon, as well as lower levels of diversity. This observation suggests that mutation and recombination are associated processes in humans, so that the positive correlation between diversity and recombination may have a purely neutral explanation. Consistent with this hypothesis, diversity levels no longer increase significantly with recombination rates after correction for divergence to chimpanzee.

Adjusting the focus on human variation

Studies of nuclear sequence variation are accumulating, such that we can expect a good description of the structure of human variation across populations and genomic regions in the near future. This description will help to elucidate the evolutionary forces that shape patterns of variability. Such an understanding will be of general biological interest, but could also facilitate the design and interpretation of disease-mapping studies. Here, we integrate the results from surveys of nuclear sequence variation. When nuclear sequences are considered together with mtDNA and microsatellites, it becomes clear that neither the standard neutral model, nor a simple long-term exponential growth model, can account for all the available human variation data. A possible explanation is that a subset of loci are not evolving neutrally; even so, more-complex models of effective population size and structure might be necessary to explain the data.

Fine-scale recombination patterns differ between chimpanzees and humans

Recombination rates seem to vary extensively along the human genome. Pedigree analysis suggests that rates vary by an order of magnitude when measured at the megabase scale, and at a finer scale, sperm typing studies point to the existence of recombination hotspots. These are short regions (1–2 kb) in which recombination rates are 10–1,000 times higher than the background rate. Less is known about how recombination rates change over time. Here we determined to what degree recombination rates are conserved among closely related species by estimating recombination rates from 14 Mb of linkage disequilibrium data in central chimpanzee and human populations. The results suggest that recombination hotspots are not conserved between the two species and that recombination rates in larger (50 kb) genomic regions are only weakly conserved. Therefore, the recombination landscape has changed markedly between the two species.