Biomedical subjects

Molly Przeworski

Publications and source records attributed to Molly Przeworski.

At least 19 recordsLinked to original sources

PubMed2025

Collateral mutagenesis funnels multiple sources of DNA damage into a ubiquitous mutational signature.

Mutations reflect the net effects of myriad types of damage, replication errors, and repair mechanisms, and thus are expected to differ across cell types with distinct exposures to mutagens, division rates, and cellular programs. Yet when mutations in humans are decomposed into a set of "signatures", one single base substitution signature, SBS5, is present across cell types and tissues, and predominates in post-mitotic neurons as well as male and female germlines [1-3]. The etiology of SBS5 is unknown. By modeling the processes by which mutations arise, we infer that SBS5 is the footprint of errors in DNA synthesis triggered by distinct types of DNA damage. Supporting this hypothesis, we find that SBS5 rates increase with signatures of endogenous and exogenous DNA damage in cancerous and non-cancerous cells and co-vary with repair rates along the genome as expected from model predictions. These analyses indicate that SBS5 captures the output of a "funnel", through which multiple sources of damage result in a similar mutation spectrum. As we further show, SBS5 mutations arise not only from translesion synthesis but also from DNA repair, suggesting that the signature reflects the occasional, shared use of a polymerase.

Journal Article↗

PubMed2006

Combining sperm typing and linkage disequilibrium analyses reveals differences in selective pressures or recombination rates across human populations.

A previous polymorphism survey of the type 2 diabetes gene CAPN10 identified a segment showing an excess of polymorphism levels in all population samples, coinciding with localized breakdown of linkage disequilibrium (LD) in a sample of Hausa from Cameroon, but not in non-African samples. This raised the possibility that a recombination hotspot is present in all populations and we had insufficient power to detect it in the non-African data. To test this possibility, we estimated the crossover rate by sperm typing in five non-African men; these estimates were consistent with the LD decay in the non-African, but not in the Hausa data. Moreover, resequencing the orthologous region in a sample of Western chimpanzees did not show either an excess of polymorphism level or rapid LD decay, suggesting that the processes underlying the patterns observed in humans operated only on the human lineage. These results suggest that a hotspot of recombination has recently arisen in humans and has reached higher frequency in the Hausa than in non-Africans, or that there is no elevation in crossover rate in any human population, and the observed variation results from long-standing balancing selection.

Animals↗

PubMed2006

An evolutionary view of human recombination.

Recombination has essential functions in mammalian meiosis, which impose several constraints on the recombination process. However, recent studies have shown that, in spite of these roles, recombination rates vary tremendously among humans, and show marked differences between humans and closely related species. These findings provide important insights into the determinants of recombination rates and raise new questions about the selective pressures that affect recombination over different genomic scales, with implications for human genetics and evolutionary biology.

Animals↗

PubMed2006

How reliable are empirical genomic scans for selective sweeps?

The beneficial substitution of an allele shapes patterns of genetic variation at linked sites. Thus, in principle, adaptations can be mapped by looking for the signature of directional selection in polymorphism data. In practice, such efforts are hampered by the need for an accurate characterization of the demographic history of the species and of the effects of positive selection. In an attempt to circumvent these difficulties, researchers are increasingly taking a purely empirical approach, in which a large number of genomic regions are ordered by summaries of the polymorphism data, and loci with extreme values are considered to be likely targets of positive selection. We evaluated the reliability of the "empirical" approach, focusing on applications to human data and to maize. To do so, we considered a coalescent model of directional selection in a sensible demographic setting, allowing for selection on standing variation as well as on a new mutation. Our simulations suggest that while empirical approaches will identify several interesting candidates, they will also miss many--in some cases, most--loci of interest. The extent of the trade-off depends on the mode of positive selection and the demographic history of the population. Specifically, the false-discovery rate is higher when directional selection involves a recessive rather than a co-dominant allele, when it acts on a previously neutral rather than a new allele, and when the population has experienced a population bottleneck rather than maintained a constant size. One implication of these results is that, insofar as attributes of the beneficial mutation (e.g., the dominance coefficient) affect the power to detect targets of selection, genomic scans will yield an unrepresentative subset of loci that contribute to adaptations.

Africa South of the Sahara↗

PubMed2005

Genetics. Motivating hotspots.

Only recently have we begun to characterize fine-scale recombination rates in mammals. In her Perspective, Przeworski discusses the work by Myers et al. in which linkage disequilibrium data have been used to produce a high-resolution recombination map for most of the human genome. More than 25,000 putative hotspots have been identified, as well as the first motifs that appear to influence their intensity.

Animals↗

PubMed2005

Directional positive selection on an allele of arbitrary dominance.

Most models of positive directional selection assume codominance of the beneficial allele. We examine the importance of this assumption by implementing a coalescent model of positive directional selection with arbitrary dominance. We find that, for a given mean fixation time, a beneficial allele has a much weaker effect on diversity at linked neutral sites when the allele is recessive.

Algorithms↗

PubMed2005

The rise and fall of the chemoattractant receptor GPR33.

Chemokine and chemoattractant receptors are members of the large superfamily of G protein-coupled receptors (GPCR), which control leukocyte chemotaxis. In addition to their physiological role, several chemokine and chemoattractant receptors, such as CCR5 and Duffy, have been directly associated with pathogen entry. GPR33 is an orphan chemoattractant GPCR that was previously identified as a pseudogene in humans. GPR33 evolved in mammals about 125-190 million years ago. The cloning and analysis of more than 120 mammalian GPR33 orthologs from 16 of 18 eutherian orders revealed an inactivation of this chemoattractant GPCR not only in humans, but also in several great ape and rodent species. Intriguingly, in all ape and some rodent species where the inactivation occurred, samples harbored both pseudogene and intact gene variants. The analysis of over 1200 human individuals representing all major linguistic groups revealed that the intact allele of GPR33 is still present in the human population. Estimates of the age of the human alleles suggest inactivation in the past 1 million years. Similarly, analysis of more than 120 wild-caught gray rats (Rattus norvegicus), revealed that inactivation of gpr33 is worldwide fixed and occurred in less than 0.7 million years ago. The coincidental inactivation and its fixation in several species of distantly related mammalian orders suggest a selective pressure on this chemoattractant receptor gene.

Alleles↗

PubMed2005

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.

Animals↗

PubMed2005

The signature of positive selection on standing genetic variation.

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.

Biological Evolution↗

PubMed2004

Absence of the TAP2 human recombination hotspot in chimpanzees.

Recent experiments using sperm typing have demonstrated that, in several regions of the human genome, recombination does not occur uniformly but instead is concentrated in "hotspots" of 1-2 kb. Moreover, the crossover asymmetry observed in a subset of these has led to the suggestion that hotspots may be short-lived on an evolutionary time scale. To test this possibility, we focused on a region known to contain a recombination hotspot in humans, TAP2, and asked whether chimpanzees, the closest living evolutionary relatives of humans, harbor a hotspot in a similar location. Specifically, we used a new statistical approach to estimate recombination rate variation from patterns of linkage disequilibrium in a sample of 24 western chimpanzees (Pan troglodytes verus). This method has been shown to produce reliable results on simulated data and on human data from the TAP2 region. Strikingly, however, it finds very little support for recombination rate variation at TAP2 in the western chimpanzee data. Moreover, simulations suggest that there should be stronger support if there were a hotspot similar to the one characterized in humans. Thus, it appears that the human TAP2 recombination hotspot is not shared by western chimpanzees. These findings demonstrate that fine-scale recombination rates can change between very closely related species and raise the possibility that rates differ among human populations, with important implications for linkage-disequilibrium based association studies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Evidence for a complex demographic history of chimpanzees.

To characterize patterns of genomic variation in central chimpanzees (Pan troglodytes troglodytes) and gain insight into their evolution, we sequenced nine unlinked, intergenic regions, representing a total of 19,000 base pairs, in 14 individuals. When these DNA sequences are compared with homologous sequences previously collected in humans and in western chimpanzees (Pan troglodytes verus), nucleotide diversity is higher in central chimpanzees than in western chimpanzees or in humans. Consistent with a larger effective population size of central chimpanzees, levels of linkage disequilibrium are lower than in humans. Patterns of linkage disequilibrium further suggest that homologous gene conversion may be an important contributor to genetic exchange at short distances, in agreement with a previous study of the same DNA sequences in humans. In central chimpanzees, but not in western chimpanzees, the allele frequency spectrum is significantly skewed towards rare alleles, pointing to population size changes or fine-scale population structure. Strikingly, the extent of genetic differentiation between western and central chimpanzees is much stronger than what is seen between human populations. This suggests that careful attention should be paid to geographic sampling in studies of chimpanzee genetic variation.

Alleles↗

PubMed2004

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.

Alouatta↗

PubMed2004

Insights into recombination from patterns of linkage disequilibrium in humans.

An ability to predict levels of linkage disequilibrium (LD) between linked markers would facilitate the design of association studies and help to distinguish between evolutionary models. Unfortunately, levels of LD depend crucially on the rate of recombination, a parameter that is difficult to measure. In humans, rates of genetic exchange between markers megabases apart can be estimated from a comparison of genetic and physical maps; these large-scale estimates can then be interpolated to predict LD at smaller ("local") scales. However, if there is extensive small-scale heterogeneity, as has been recently proposed, local rates of recombination could differ substantially from those averaged over much larger distances. We test this hypothesis by estimating local recombination rates indirectly from patterns of LD in 84 genomic regions surveyed by the SeattleSNPs project in a sample of individuals of European descent and of African-Americans. We find that LD-based estimates are significantly positively correlated with map-based estimates. This implies that large-scale, average rates are informative about local rates of recombination. Conversely, although LD-based estimates are based on a number of simplifying assumptions, it appears that they capture considerable information about the underlying recombination rate or at least about the ordering of regions by recombination rate. Using LD-based estimators, we also find evidence for homologous gene conversion in patterns of polymorphism. However, as we demonstrate by simulation, inferences about gene conversion are unreliable, even with extensive data from homogeneous regions of the genome, and are confounded by genotyping error.

Chromosome Mapping↗

PubMed2003

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.

Animals↗

PubMed2003

Estimating the time since the fixation of a beneficial allele.

The fixation of a beneficial allele in a population leaves a well-characterized signature in patterns of nucleotide variation at linked sites. This signature can be used to estimate the time since fixation from patterns of polymorphism in extant individuals. I introduce a method to assess the support in polymorphism data for a recent episode of directional positive selection and to estimate the time since fixation. I summarize the polymorphism data by three statistics that carry information about levels of diversity, the allele frequency spectrum, and the extent of allelic associations. Simulations are then used to obtain a sample from the posterior distribution of the time since fixation, conditional on the observed summaries. I test the performance of the approach on simulated data and apply it to the gene tb1 in maize. The data support the recent fixation of a favored allele, consistent with what is known about the importance of tb1 in the domestication process of maize.

Algorithms↗

PubMed2002

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.

Alleles↗

PubMed2002

Evidence for positive selection and population structure at the human MAO-A gene.

We report the analysis of human nucleotide diversity at a genetic locus known to be involved in a behavioral phenotype, the monoamine oxidase A gene. Sequencing of five regions totaling 18.8 kb and spanning 90 kb of the monoamine oxidase A gene was carried out in 56 male individuals from seven different ethnogeographic groups. We uncovered 41 segregating sites, which formed 46 distinct haplotypes. A permutation test detected substantial population structure in these samples. Consistent with differentiation between populations, linkage disequilibrium is higher than expected under panmixia, with no evidence of a decay with distance. The extent of linkage disequilibrium is not typical of nuclear loci and suggests that the underlying population structure may have been accentuated by a selective sweep that fixed different haplotypes in different populations, or by local adaptation. In support of this suggestion, we find both a reduction in levels of diversity (as measured by a Hudson-Kreitman-Aguade test with the DMD44 locus) and an excess of high frequency-derived variants, as expected after a recent episode of positive selection.

Animals↗

PubMed2002

Evidence for population growth in humans is confounded by fine-scale population structure.

Although many studies have reported human polymorphism data, there has been no analysis of the effect of sampling design on the patterns of variability recovered. Here, we consider which factors affect a summary of the allele-frequency spectrum. The most important variable to emerge from our analysis is the number of ethnicities sampled: studies that sequence individuals from more ethnicities recover more rare alleles. These observations are consistent with fine-scale geographic differentiation as well as population growth. They suggest that the geographic sampling strategy should be considered carefully, especially when the aim is to infer the demographic history of humans.

Humans↗