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Why do human germline mutation rates depend on age and sex?

Germline mutation is the source of all heritable differences and therefore of fundamental importance. In mammals, it has long been appreciated that mutation rates are higher in fathers, particularly older fathers. The textbook view has been that these patterns reflect replication errors that accrue during spermatogenesis. I will present multiple lines of evidence that call this view into question. I will argue instead that the data are best explained by a much larger role of DNA damage in the genesis of germline mutations than previously appreciated, and draw implications for why mutation rates depend on sex and age and how they evolve over time.

Molly Przeworski, Alan H. Kempner Professor of Biological Sciences & Systems Biology

Molly Przeworski is a population geneticist at Columbia University. She is interested in the evolutionary roots of heritable variation within and between species. Her research focuses primarily on the two processes that generate genetic variation, mutation and recombination, and why they differ among vertebrate species. Research in her lab has also clarified how natural selection operates in human populations: notably, it has demonstrated that few recent human adaptations involved new, single changes of large effect and helped characterize the footprints of other forms of adaptation in genetic variation data. In parallel, her group has worked on mapping trait variation to the genome, both to investigate what associations are being detected in humans and to extend the approach to non-model organisms subject to strong selection pressures from climate change.

Molly received a B.A. in Mathematics from Princeton University and a Ph.D. from the Committee on Evolutionary Biology at the University of Chicago, then conducted postdoctoral research in the Statistics Department of the University of Oxford. Before moving to Columbia University, she was a researcher at the Max Planck Institute for Evolutionary Anthropology and a faculty member at Brown University and the University of Chicago. Her work has been recognized by the Rosalind Franklin Award, a Sloan Research Fellowship, a Howard Hughes Medical Institute Early Career Scientist Award, and the 2023 Scientific Achievement Award from the American Society of Human Genetics, as well as election to the American Academy of Arts and Sciences and National Academy of Sciences.

Symposia Lecture: Data-driven insights into variant-to-function mechanisms in human traits and diseases

Genome-wide characterization of molecular and cellular effects of genetic variants is essential for understanding biological processes that underlie genetic associations to disease. This can be pursued by many approaches: population genetic approaches that associate genetic variation to molecular phenotypes, large-scale CRISPR perturbations coupled with single-cell readouts, and predictive models of variant effects. Our work shows how complementary insights from joint application of multiple tools uncovers functional genetic architecture of human traits. This has applications both for fundamental understanding of genome biology, mechanisms underlying human disease, and future applications in precision medicine.

Professor Tuuli Lappalainen

Tuuli Lappalainen, PhD, is a Professor at KTH Royal Institute of Technology, the Director of the Genomics Platform and the National Genomics Infrastructure of SciLifeLab, and a Senior Associate Faculty Member at the New York Genome Center. Her research uses both population genomics and CRISPR tools to characterize molecular and cellular effects of genetic variation and their contribution to human traits and diseases. Dr. Lappalainen has contributed to many international research consortia in human genetics and genomics and has received multiple prizes for her contributions to the field.

Symposia Lecture: Homo sapiens specific genetic variants and the importance of ancient southern African genomes

Genetic variants unique to our species -- Homo sapiens – are key to the evolution of our species and important for advancing our understanding of human genomic variation. H. sapiens evolved hundreds of thousands of years ago in Africa, later spreading across the globe, but the early evolutionary process is debated. Southern Africa has a rich paleoanthropological and archaeological record, including the oldest artifacts indicating symbolic thinking. Recent genomic studies of ancient southern Africans reveal long-term isolation in the region and a genetic make-up outside the range of modern-day humans. We have recently sequenced several complete genomes of ancient southern Africans, some dating back to 10,000 years ago, redefining the catalogue of ‘sapiens-specific’ variants. I will discuss how such ‘sapiens-specific’ variants likely evolved rapidly on the sapiens branch, and give a few examples of amino-acid-altering sites fixed for all humans, also for the ancient southern Africans. Such variants were enriched for genes associated with kidney-function, likely impacting water-retention, and possibly linked to the human-unique trait of endurance and temperature-control via perspiration. Other enriched gene-categories include genes affecting the immune system and cognitive functions. I will conceptually outline how these ancient southern African genomes will help us understand early H. sapiens evolution and the origins of our species.

Professor Mattias Jakobsson

Mattias Jakobsson is a professor of Genetics and the head of the Human Evolution research program at Uppsala University. Jakobsson’s research spans from population genetics, human evolution, and human history. His lab uses computational approaches for deciphering complex patterns of large-scale human genomic variation from both modern-day and ancient humans in order to understand human evolutionary history. The lab focuses on interrogating long-standing questions in human evolution, including pioneering studies that resolved the enigma of the Neolithic expansion in Europe, and studies that redefined and doubled the age of modern humans. Jakobsson has published more than 140 peer-reviewed articles, and his work has been cited more than 32,000 times. Jakobsson has been a Wallenberg Scholar since 2020, leads the excellence center on the Human Past, and has led several large research projects funded by the ERC, Knut and Alice Wallenberg foundation and the Swedish Research council. He is the Dean of Biology at Uppsala University and has received the Tage Erlander prize and the Göran Gustafsson prize from the Royal Academy of Sweden, the Linné medal in gold from Uppsala University and the Thuéus prize from the Royal Society of Sciences at Uppsala.