2023 ASHG Scientific Achievement Award

This article is based on the address given by the author at the 2023 meeting of The American Society of Human Genetics (ASHG) in Washington, D.C. A video of the original address can be found at the ASHG website. This article is based on the address given by the author at the 2023 meeting of The American Society of Human Genetics (ASHG) in Washington, D.C. A video of the original address can be found at the ASHG website. Thank you for the kind introduction. I am deeply honored to receive this award, and on this occasion even more than usual, I am grateful to the many people who have helped me along the way. Most obviously, to Jay Shendure, who wrote me out of the blue to say that he had nominated me and to wish me luck, and to the Awards committee. I would also like to thank my letter writers, Sally Otto, Andy Clark, and Aravinda Chakravarti, for many years of wise counsel and unstinting support. My research group is interested in exploring the evolutionary roots of genetic variation: how genetic differences among humans arose, and how and why they are maintained. For over a century now, we have known that genetic variation arises from two genetic processes, mutation and recombination, and is shaped by two population processes, the demographic history of our ancestors and the selective pressures to which they were subject.1Provine W.B. Origins of theoretical population genetics. University of Chicago Press, Chicago, IL2001Crossref Google Scholar Over the past 20 years, we have begun to have the data to finally characterize these different forces and evaluate their relative importance.2Przeworski M. Hudson R.R. Di Rienzo A. Adjusting the focus on human variation.Trends Genet. 2000; 16: 296-302Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar This means that we can aim to build a ground-up, comprehensive understanding of genetic variation: for instance, to understand not just how, but why, trait variation is often so polygenic3Boyle E.A. Li Y.I. Pritchard J.K. An Expanded View of Complex Traits: From Polygenic to Omnigenic.Cell. 2017; 169: 1177-1186Abstract Full Text Full Text PDF PubMed Scopus (1651) Google Scholar,4Sella G. Barton N.H. Thinking About the Evolution of Complex Traits in the Era of Genome-Wide Association Studies.Annu. Rev. Genomics Hum. Genet. 2019; 20: 461-493Crossref PubMed Scopus (117) Google Scholar; why some disease mutations are more frequent in populations than others5Amorim C.E.G. Gao Z. Baker Z. Diesel J.F. Simons Y.B. Haque I.S. Pickrell J. Przeworski M. The population genetics of human disease: The case of recessive, lethal mutations.PLoS Genet. 2017; 13e1006915Crossref Scopus (29) Google Scholar; or what fraction of heritable human variation is under selection.6Chakravarti A. Commentary: The central questions of human genetics: Richard Lewontin's 1968 senior lecture in Victor McKusick's Bar Harbor short course.Int. J. Epidemiol. 2016; 45: 668-672Crossref PubMed Scopus (1) Google Scholar Over the past decade, my lab has been especially interested in the processes by which new variants arise: mutation and recombination. What is particularly exciting about working in this area is that some basic questions remain unanswered.7Ségurel L. Wyman M.J. Przeworski M. Determinants of mutation rate variation in the human germline.Annu. Rev. Genomics Hum. Genet. 2014; 15: 47-70Crossref PubMed Scopus (198) Google Scholar,8Moorjani P. Gao Z. Przeworski M. Human Germline Mutation and the Erratic Evolutionary Clock.PLoS Biol. 2016; 14e2000744Crossref PubMed Scopus (40) Google Scholar To give one example, it was long believed that the sex bias in germline mutation—the fact that fathers transmit more point mutations than mothers—reflects the many cell divisions that give rise to sperm of older fathers.9Crow J.F. The origins, patterns and implications of human spontaneous mutation.Nat. Rev. Genet. 2000; 1: 40-47Crossref PubMed Scopus (683) Google Scholar Yet, as my lab showed, the sex bias in mutation is actually very similar in parents of different ages,10Gao Z. Moorjani P. Sasani T.A. Pedersen B.S. Quinlan A.R. Jorde L.B. Amster G. Przeworski M. Overlooked roles of DNA damage and maternal age in generating human germline mutations.Proc. Natl. Acad. Sci. USA. 2019; 116: 9491-9500Crossref PubMed Scopus (107) Google Scholar and also across mammals with drastically different reproductive lifespans.11Wu F.L. Strand A.I. Cox L.A. Ober C. Wall J.D. Moorjani P. Przeworski M. A comparison of humans and baboons suggests germline mutation rates do not track cell divisions.PLoS Biol. 2020; 18e3000838Crossref Google Scholar,12de Manuel M. Wu F.L. Przeworski M. A paternal bias in germline mutation is widespread in amniotes and can arise independently of cell division numbers.Elife. 2022; 11Crossref PubMed Scopus (13) Google Scholar More generally, our analyses suggest that contrary to what was long believed, most germline mutations do not track cell divisions, and instead arise from damage that is incorrectly repaired.13Spisak N. de Manuel M. Milligan W. Sella G. Przeworski M. Disentangling sources of clock-like mutations in germline and soma.bioRxiv. 2023; https://doi.org/10.1101/2023.09.07.556720v1Crossref Google Scholar Along with Bernard de Massy, Peter Donnelly, Anjali Hinch, Gil McVean, Simon Myers, and many others, we have also worked toward understanding how recombination events are directed to our genome during meiosis. We now know that in humans, it is the binding of PRDM9 that specifies the location of almost all recombination events, and that turnover in PRDM9 binding affinity drives the rapid evolution of recombination hotspots within humans and between species.14Baudat F. Buard J. Grey C. Fledel-Alon A. Ober C. Przeworski M. Coop G. de Massy B. PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice.Science. 2010; 327: 836-840Crossref PubMed Scopus (721) Google Scholar,15Myers S. Bowden R. Tumian A. Bontrop R.E. Freeman C. MacFie T.S. McVean G. Donnelly P. Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination.Science. 2010; 327: 876-879Crossref PubMed Scopus (493) Google Scholar,16Hinch A.G. Zhang G. Becker P.W. Moralli D. Hinch R. Davies B. Bowden R. Donnelly P. Factors influencing meiotic recombination revealed by whole-genome sequencing of single sperm.Science. 2019; 363https://doi.org/10.1126/science.aau8861Crossref PubMed Scopus (64) Google Scholar,17Auton A. Fledel-Alon A. Pfeifer S. Venn O. Ségurel L. Street T. Leffler E.M. Bowden R. Aneas I. Broxholme J. et al.A fine-scale chimpanzee genetic map from population sequencing.Science. 2012; 336: 193-198Crossref PubMed Scopus (210) Google Scholar,18Altemose N. Noor N. Bitoun E. Tumian A. Imbeault M. Chapman J.R. Aricescu A.R. Myers S.R. A map of human PRDM9 binding provides evidence for novel behaviors of PRDM9 and other zinc-finger proteins in meiosis.Elife. 2017; 6https://doi.org/10.7554/eLife.28383Crossref PubMed Scopus (55) Google Scholar We have also learned that other vertebrates, such as dogs or birds, lack PRDM9 and instead use other strategies, which result in more stable recombination landscapes.19Singhal S. Leffler E.M. Sannareddy K. Turner I. Venn O. Hooper D.M. Strand A.I. Li Q. Raney B. Balakrishnan C.N. et al.Stable recombination hotspots in birds.Science. 2015; 350: 928-932Crossref PubMed Scopus (183) Google Scholar,20Auton A. Rui Li Y. Kidd J. Oliveira K. Nadel J. Holloway J.K. Hayward J.J. Cohen P.E. Greally J.M. Wang J. et al.Genetic recombination is targeted towards gene promoter regions in dogs.PLoS Genet. 2013; 9e1003984Crossref PubMed Scopus (136) Google Scholar In yet other species, such as snakes, it turns out that the different strategies co-exist.21Hoge C. de Manuel M. Mahgoub M. Okami N. Fuller Z. Banerjee S. Baker Z. McNulty M. Andolfatto P. Macfarlan T.S. et al.Patterns of recombination in snakes reveal a tug of war between PRDM9 and promoter-like features.bioRxiv. 2023; https://doi.org/10.1101/2023.07.11.548536v1Crossref Google Scholar In parallel, we have worked toward a better understanding of the dynamics of natural selection in humans. Together with Graham Coop, Joe Pickrell, Jonathan Pritchard, and Guy Sella, we showed that most human adaptations do not act on single new mutations of large effect that rapidly rise in frequency until they fix in the population.22Hernandez R.D. Kelley J.L. Elyashiv E. Melton S.C. Auton A. McVean G. Sella G. Przeworski M. 1000 Genomes ProjectClassic selective sweeps were rare in recent human evolution.Science. 2011; 331: 920-924Crossref PubMed Scopus (317) Google Scholar,23Pritchard J.K. Pickrell J.K. Coop G. The genetics of human adaptation: hard sweeps, soft sweeps, and polygenic adaptation.Curr. Biol. 2010; 20: R208-R215Abstract Full Text Full Text PDF PubMed Scopus (627) Google Scholar Instead, human adaptations on most traits of interest likely involved concomitant selection on many alleles of much smaller effect. These findings shifted the focus toward the dynamics of polygenic adaptation and motivated current efforts to use GWAS findings to elucidate how adaptations played out over human evolution and across the globe.24Harpak A. Przeworski M. The evolution of group differences in changing environments.PLoS Biol. 2021; 19e3001072Crossref PubMed Scopus (24) Google Scholar,25Mostafavi H. Berisa T. Day F.R. Perry J.R.B. Przeworski M. Pickrell J.K. Identifying genetic variants that affect viability in large cohorts.PLoS Biol. 2017; 15e2002458Crossref PubMed Scopus (47) Google Scholar,26Berg J.J. Coop G. A population genetic signal of polygenic adaptation.PLoS Genet. 2014; 10e1004412Crossref Scopus (315) Google Scholar,27Edge M.D. Coop G. 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Dev. 2020; 62: 97-104Crossref PubMed Scopus (18) Google Scholar Much of the work I describe has been done since I moved to Columbia University, now 10 years ago. But I'd like to take this opportunity to go back in time and acknowledge some of the many people who contributed to my professional fortunes—and beyond that, to highlight the central role of luck, and of solidarity, in scientific success. I would never even have studied genetics had I not reached out to Brian Charlesworth, who took a chance on me when I knew no biology, and thanks to whom I was accepted into exactly one of the six graduate programs to which I applied. The University of Chicago Ecology and Evolution Department that I entered as a PhD student turned out to be an unrivaled environment in which to be introduced to population and quantitative genetics, in part because of Brian and Deborah Charlesworth, my advisor Richard Hudson, Marty Kreitman, and other faculty members, but also because of the amazing cohort of graduate students and postdocs among whom I landed, including Peter Andolfatto, Magnus Nordborg, and Jeff Wall. In particular, it is to Jeff that I owe my entrance into human evolution and genetics; I am grateful to him for a few key pep talks, and much more. My good luck continued when in the last year of my PhD, Jonathan Pritchard came through to give a talk, and he encouraged me to join him, Matthew Stephens, and others as a postdoc with Peter Donnelly at Oxford. That too was an exceptional constellation of people—including Simon Myers and Graham Coop, who were PhD students at the time, Gil McVean, who had just started as a faculty member, and many more—and an exciting time for human and statistical genetics. The intellectual experience of the community has shaped my thinking ever since. A few years later I was reunited with Jonathan and Matthew as a faculty member in the Human Genetics Department at the University of Chicago, where we ran labs side by side for several years. That department was founded by Nancy Cox, Anna Di Rienzo, Carole Ober, and others a quarter century ago. From the start, it fostered a unique conversation between human and population genetics. Yet again, I was very lucky: I found myself in a vibrant, collegial department with high standards and a real sense of intellectual excitement. That environment was nurtured and protected by the chairs, Conrad Gilliam and Carole Ober. Now that I no longer take what they managed to pull off for granted, I realize just how much I owe to the good fortune of starting my career there, and in particular to Carole and Anna. I would also like to thank Jonathan for being an inspiring colleague and loyal friend for many decades now; it's hard to imagine what my scientific path would have been like had he not accompanied me along it. Graham Coop and Guy Sella have also been huge influences on my work and great friends over the years. Finally, I also owe an immense debt of gratitude to the more than 40 people from all over the world who somehow made their way to my lab. As is sometimes not well appreciated, science is fundamentally a social activity: one that, at its best, offers people from every background a common language and shared mysteries to solve. I have enjoyed this aspect of our work most of all, and I am grateful to past and present lab members for countless discussions, arguments, and explanations—and when all else failed, for their senses of humor.