Biology subjects

Molly Przeworski

Publications and source records attributed to Molly Przeworski.

6 recordsLinked to original sources

bioRxiv2016

Human germline mutation and the erratic evolutionary clock

Our understanding of the chronology of human evolution relies on the \"molecular clock\" provided by the steady accumulation of substitutions on an evolutionary lineage. Recent analyses of human pedigrees have called this understanding into question, by revealing unexpectedly low germline mutation rates, which imply that substitutions accrue more slowly than previously believed. Translating mutation rates estimated from pedigrees into substitution rates is not as straightforward as it may seem, however. We dissect the steps involved, emphasizing that dating evolutionary events requires not \"a mutation rate,\" but a precise characterization of how mutations accumulate in development, in males and females--knowledge that remains elusive.

Evolutionary Biology↗

bioRxiv2016

Variation in the molecular clock of primates

Events in primate evolution are often dated by assuming a \"molecular clock\", i.e., a constant rate of substitution per unit time, but the validity of this assumption remains unclear. Among mammals, it is well known that there exists substantial variation in yearly substitution rates. Such variation is to be expected from differences in life-history traits, suggesting that it should also be found among primates. Motivated by these considerations, we analyze whole genomes from ten primate species, including Old World Monkeys (OWMs), New World Monkeys (NWMs) and apes, focusing on putatively neutral autosomal sites and controlling for possible effects of biased gene conversion and methylation at CpG sites. We find that substitution rates are {small tilde}65% higher in lineages leading from the hominoid-NWM ancestor to NWMs than to apes. Within apes, rates are {small tilde}2% higher in chimpanzees and {small tilde}7% higher in the gorilla than in humans. Substitution types subject to biased gene conversion show no more variation among species than those not subject to it. Not all mutation types behave similarly, however: in particular, transitions at CpG sites exhibit a more clock-like behavior than do other types, presumably due to their non-replicative origin. Thus, not only the total rate, but also the mutational spectrum varies among primates. This finding suggests that events in primate evolution are most reliably dated using CpG transitions. Taking this approach, we estimate that the average time to the most recent common ancestor of human and chimpanzee is 12.1 million years and their split time 7.9 million years.\n\nSignificance statementMuch of our understanding of the chronology of human evolution relies on the \"molecular clock\", i.e., a constant rate of substitutions per unit time. To evaluate the validity of this assumption, we analyze whole genome sequences from ten primate species. We find that there is substantial variation in the molecular clock between apes and monkeys, and rates even differ within hominoids. Importantly, not all mutation types behave similarly: notably, transitions at CpG sites exhibit a more clock-like behavior than other substitutions, presumably due to their non-replicative origin. Thus, the mutation spectra, and not just the overall substitution rates, are changing across primates. This finding further suggests that events in primate evolution are most reliably dated using CpG transitions.

Evolutionary Biology↗

bioRxiv2015

Dating ancient human samples using the recombination clock

The study of human evolution has been revolutionized by inferences from ancient DNA analyses. Key to these is the reliable estimation of the age of ancient specimens. The current best practice is radiocarbon dating, which relies on characterizing the decay of radioactive carbon isotope (14C), and is applicable for dating up to 50,000-year-old samples. Here, we introduce a new genetic method that uses recombination clock for dating. The key idea is that an ancient genome has evolved less than the genomes of extant individuals. Thus, given a molecular clock provided by the steady accumulation of recombination events, one can infer the age of the ancient genome based on the number of missing years of evolution. To implement this idea, we take advantage of the shared history of Neanderthal gene flow into non-Africans that occurred around 50,000 years ago. Using the Neanderthal ancestry decay patterns, we estimate the Neanderthal admixture time for both ancient and extant samples. The difference in these admixture dates then provides an estimate of the age of the ancient genome. We show that our method provides reliable results in simulations. We apply our method to date five ancient Eurasian genomes with radiocarbon dates ranging between 12,000 to 45,000 years and recover consistent age estimates. Our method provides a complementary approach for dating ancient human samples and is applicable to ancient non-African genomes with Neanderthal ancestry. Extensions of this methodology that use older shared events may be able to date ancient genomes that fall beyond the radiocarbon frontier.\n\nSignificanceWe introduce a new genetic method for dating ancient human samples that uses the recombination clock. The main idea relies on the insight that an ancient genome lacks several thousand years of evolution compared to genomes of living individuals. To infer the age of ancient genomes, we take advantage of the shared history of Neanderthal gene flow into non-Africans that occurred around 50,000 years ago. By characterizing the dates of Neanderthal gene flow in ancient and extant genomes and quantifying the difference in these dates, we estimate the age of the ancient specimen. Our method is applicable for dating ancient samples more recent than the Neanderthal mixture event, so on par with radiocarbon dating, providing a complementary approach for dating.

Evolutionary Biology↗

bioRxiv2015

Stable recombination hotspots in birds

Although the DNA-binding protein PRDM9 plays a critical role in the specification of meiotic recombination hotspots in mice and apes, it appears to be absent from many vertebrate species, including birds. To learn about the determinants of fine-scale recombination rates and their evolution in natural populations lacking PRDM9, we inferred fine-scale recombination maps from population resequencing data for two bird species, the zebra finch Taeniopygia guttata, and the long-tailed finch, Poephila acuticauda, whose divergence is on par with that between human and chimpanzee. We find that both bird species have hotspots, and these are enriched near CpG islands and transcription start sites. In sharp contrast to what is seen in mice and apes, the hotspots are largely shared between the two species, with indirect evidence of conservation extending across bird species tens of millions of years diverged. These observations link the evolution of hotspots to their genetic architecture, suggesting that in the absence of PRDM9 binding specificity, accessibility of the genome to the cellular recombination machinery, particularly around functional genomic elements, both enables increased recombination and constrains its evolution.

Evolutionary Biology↗

bioRxiv2015

Variation in rural African gut microbiota is strongly correlated with colonization by Entamoeba and subsistence

The human gut microbiota is impacted by host nutrition and health status and therefore represents a potentially adaptive phenotype influenced by metabolic and immune constraints. Previous studies contrasting rural populations in developing countries to urban industrialized ones have shown that industrialization is strongly correlated with patterns in human gut microbiota; however, we know little about the relative contribution of factors such as climate, diet, medicine, hygiene practices, host genetics, and parasitism. Here, we focus on fine-scale comparisons of African rural populations in order to (i) contrast the gut microbiota of populations inhabiting similar environments but having different traditional subsistence modes and either shared or distinct genetic ancestry, and (ii) examine the relationship between gut parasites and bacterial communities. Characterizing the fecal microbiota of Pygmy hunter-gatherers as well as Bantu individuals from both farming and fishing populations in Southwest Cameroon, we found that the gut parasite Entamoeba is significantly correlated with microbiome composition and diversity. We show that across populations, colonization by this protozoa can be predicted with 79% accuracy based on the composition of an individual's gut microbiota, and that several of the taxa most important for distinguishing Entamoeba absence or presence are signature taxa for autoimmune disorders. We also found gut communities to vary significantly with subsistence mode, notably with some taxa previously shown to be enriched in other hunter-gatherers groups (in Tanzania and Peru) also discriminating hunter-gatherers from neighboring farming or fishing populations in Cameroon.\n\nAuthor SummaryThe community of microorganisms inhabiting the gastrointestinal tract plays a critical role in determining human health. Its been hypothesized that the industrialized lifestyle, marked by a diet rich in processed foods, higher use of antibiotics, increased hygiene, and exposure to various chemicals, has altered microbiota in ways that are harmful. Studies have addressed this by comparing rural and industrialized populations, and have found that they systematically vary in their gut microbiome composition. Nevertheless, the relative influence of host genetics, diet, climate, medication, hygiene practices, and parasitism is still not clear. In addition, microbial variation between nearby human populations has not been explored in depth. Moreover, The World Health Organization estimates that 24% of the worlds population, concentrated in developing countries, is infected with gut parasites. Despite this, and evidence for direct interactions between the immune system and both gut parasites and bacteria, we know relatively little about the relationship between gut helminths, protozoa, and bacteria. In our study, we aimed to address some of this complexity. To do so, we characterized the gut microbial communities and parasites from Pygmy hunter-gatherer and Bantu farming and fishing populations from seven locations in the rainforest of Southwest Cameroon. We found that both subsistence mode and the presence of the gut protozoa, Entamoeba, were significantly correlated with microbiome composition. These findings support previous studies demonstrating diet is an important determinant of gut microbiota, and further show that this pattern holds true at a local scale, in traditional societies inhabiting a similar environment. Additionally, we show a significant relationship between a common human parasite (Entamoeba) and gut bacterial community composition, suggesting potential important interactions between the immune system, gut bacteria, and gut parasites, highlighting the need for more hierarchical cross population studies that include parasitism as potential factor influencing gut microbiota dynamics.

Microbiology↗

bioRxiv2014

Non-crossover gene conversions show strong GC bias and unexpected clustering in humans

Although the past decade has seen tremendous progress in our understanding of fine-scale recombination, little is known about non-crossover (NCO) gene conversion. We report the first genome-wide study of NCO events in humans. Using SNP array data from 98 meioses, we identified 103 sites affected by NCO, of which 50/52 were confirmed in sequence data. Overlap with double strand break (DSB) hotspots indicates that the events are likely of meiotic origin. We estimate that a site is involved in a NCO at a rate of 5.7x10-6/bp/generation, consistent with sperm-typing studies, and infer that tract lengths span at least an order of magnitude. Observed NCO events show strong allelic bias at heterozygous AT/GC SNPs, with 68% (58-78%) transmitting GC alleles (P=5x10-4). Strikingly, in 4 of 15 regions for which there are also resequencing data, multiple disjoint NCO tracts cluster in close proximity (~20-30 kb), a phenomenon not previously seen in mammals.

Genetics↗