September 6th, Friday @ BROAD - Monadnock [ In Person Only ]
- Registration is required -
8:50AM - Breakfast / Welcome [Organizers]
9:00AM - 1) Javier Maravall-López : Reich lab
- Title: Fine-mapped SNP and indel variants under directional selection reveal the functional architecture of human adaptation
- Summary: The exponentially increasing number of available ancient genomes has been transformative to our understanding of human population history, but studies of adaptation have lagged behind. However, a recent breakthrough study by Ali Akbari from the Reich laboratory and colleagues has realized its potential by uncovering hundreds of independent targets of natural selection in Holocene Western Eurasia. Here, we fine-map these selected variants and analyze their functional architecture to understand what variant classes were the primary actors of adaptation. In the first place, we find significant enrichment across a large number of functional annotations. In the second place, we find indel variants to be significantly enriched at a PIP threshold of 0.95, suggestive of this variant class having on average a higher phenotypic impact than SNPs. Finally, motivated by this observation, we perform PheWAS and co-localization analysis to identify several indels that are the top fine-mapped candidates simultaneously for natural selection and several GWAS traits, consistent with having been favored by selection. Our work identifies the functional components of human adaptation in Holocene Western Eurasia, while broadening our understanding of the general role that indel variation may play in human complex traits.
9:20AM - 2) Ekaterina Osipova : Sackton lab
- Title: Comparative population genomics reveals convergent signatures of adaptation in avian brood parasites
- Summary: Parental care is a widespread behavioral strategy in the animal kingdom that plays a crucial role in the offspring survival. Nevertheless, brood parasitism, in which parasitic species exploit hosts to provide parental care and raise their young, has evolved seven independent times in birds. The evolution of obligate brood parasitism is a radical life history transition, which is currently poorly understood at the genetic level. To study genetic patterns of recent adaptation associated with avian brood parasitism, we have generated population-scale resequencing data (n = 11-31 individuals per species) from five species of obligate brood parasites along with their nesting outgroups. These species include the cuckoo finches and wydahs, the greater honeyguide, and the brown-headed cowbird, which together represent three independent origins of brood parasitism. Using McDonald–Kreitman framework, we find evidence for repeated adaptation in genes involved in spermatogenesis and sperm function in multiple parasitic clades, but not in their sister, nesting clades. This is consistent with evidence for increased male-male competition in parasitic lineages as a result of allocating resources from parental investment to reproduction. In addition, we find evidence of recent selective sweeps near genes associated with nervous system development in parasitic lineages, potentially contributing to the increased spatial navigation skills in brood parasites necessary to locate and surveil hosts’ nests.
9:40AM - 3) Haoran Cai : Des Marais lab
- Title: Dissecting genetic correlation and pleiotropy through a genetic cross
- Summary: Pleiotropy, the phenomenon of a single gene or mutation influencing multiple phenotypic traits, has profound implications in genetics, evolution, and medicine. Genetic correlation between traits driven by pleiotropy represents a crucial class of evolutionary constraints and is well studied. Classical evolutionary quantitative genetic theory often assumes a static genetic covariance structure over relevant evolutionary timeframes, yet this structure is itself evolvable. Empirical evidence on the evolution of genetic correlations remains inconclusive, hindering our ability to predict the outcome of selection. A fundamental understanding of the mechanisms driving genetic correlations is thus essential to ascertain their persistence and predictive power in long-term evolutionary divergence. Natural selection may favor certain combinations of traits and thereby lead to genetic correlation via pleiotropy. However, genetic correlations may also be influenced by intrinsic organismal attributes, termed developmental bias. Much confusion and controversy remain over the definitions of developmental bias, and identifying it is notoriously challenging. Here, we propose a framework to dissect genetic correlation and ask whether the absence of certain combinations of traits, as indicated by genetic correlation, reflects developmental bias. Through empirical analyses, we find that our approach can distinguish whether genetically correlated traits are developmentally constrained to covary. Our framework presents a feasible way to dissect the mechanisms underlying genetic correlation and pleiotropy.
10:00AM - 4) Elizabeth Hemenway : Gehring lab
- Title: ROS1 antagonizes parent-of-origin specific DNA methylation in the endosperm
- Summary: The endosperm is a second product of fertilization in seeds that provides nutrients for the developing embryo. As such, the endosperm is both essential for plant reproduction and provides an important source of calories for humans and animals. The endosperm also has a unique genetic and epigenetic landscape, in part shaped by active removal of 5-methylcytosine (DNA methylation) prior to fertilization. In the model plant Arabidopsis thaliana, two DNA demethylases, ROS1 and DME, are largely sufficient for proper DNA demethylation across the Arabidopsis genome. DME is active in the female progenitor cell of the endosperm prior to fertilization and is required for endosperm viability and thus reproduction. Through restricted activity in the female gametophyte and not the male gametophyte during reproduction, DME promotes parent-of-origin specific DNA methylation in the endosperm. Unlike DME, ROS1 is not an essential gene but is expressed broadly across plant tissues, including the endosperm. However, the role of ROS1 in endosperm, if any, has been largely unexplored. We used whole-genome enzymatic-methyl sequencing (EM-seq) of wild-type and ros1 mutant endosperm to assess the contribution of ROS1 to endosperm DNA methylation patterning. We found ROS1 is required to prevent aberrant gain of methylation at several hundred sites in endosperm, and these sites are mostly the same as ROS1 targets in other tissues. However, we found that ROS1 target loci have a reduced capacity for hypermethylation in ros1 mutant endosperm relative to leaf. We hypothesized this might be due to biased effects of ROS1 on either the maternally or paternally inherited genome. To test this hypothesis, we performed EM-seq on F1 hybrids of distinct Arabidopsis strains in a ros1 background. We observed that ROS1-dependent DNA demethylation occurs primarily on paternally inherited alleles. Given the established role of DME in maternal genome demethylation, future work will be focused on the molecular and genetic relationship between DME and ROS1 in the endosperm and how this could inform our understanding of parental conflict and evolution of gene imprinting in the seed.
10:20AM - 5) Alexander Okamoto : Capellini Lab
- Title: Parallel evolution at the regulatory base-pair level contributes to mammalian inter-specific differences in polygenic traits
- Summary: Parallel evolution occurs when distinct lineages with similar ancestral states converge on a new phenotype. Parallel evolution has been well documented at the organ, gene pathway, and amino-acid sequence level but in theory it can also occur at individual nucleotides within non-coding regions. To examine the role of parallel evolution in shaping the biology of mammalian complex traits, we used data on single nucleotide polymorphisms (SNPs) influencing human intraspecific variation to predict trait values in other species for eleven complex traits. We found that the alleles at SNP positions associated with human intraspecific height and red blood cell count variation are associated with interspecific variation in the corresponding traits across mammals. These associations hold for deeper branches of mammalian evolution as well as between strains of collaborative cross mice. While variation in red blood cell count between primates uses both ancient and more recently evolved genomic regions, we found that only primate-specific elements were correlated with primate body size. We show that the SNP positions driving these signals are flanked by conserved sequences, maintain synteny with target genes, and overlap transcription factor binding sites. This work highlights the potential of conserved but tunable regulatory elements to be reused in parallel to facilitate evolutionary adaptation in mammals.
10:40AM - Coffee Break
11:00AM - *Keynote Speaker : Richard Durbin
:: Al-Kindi Professor of Genetics at the University of Cambridge / Associate Faculty Member at the Wellcome Trust Sanger Institute ::
- Title: Genome evolution driven by transposable elements across the Tree of Life
- Summary: We are on an exponential ramp towards assembling high quality reference genome sequences for all of life. It is becoming increasingly clear that while most individual mutations are single-base, more sequence is changed through structural variation, driven in large part by transposable elements (TE), frequently with greater functional and reproductive consequences. Furthermore, we are coming to see mobile elements as often symbiotic as much as parasitic, living in a genomic ecosystem with each other and their hosts. I’ll talk about TE involvement in centromeric sequence dynamics and in adaptive speciation in the Malawi cichlid radiation; and about some ideas for new approaches for studying TE-host coevolution.
12:10PM - Lunch
1:20PM - 6) Rishabh Kapoor : Extavour lab
- Title: Massive inter-metazoan horizontal gene transfer contributes to biochemical novelty in fungus gnats
- Summary: Horizontal gene transfer (HGT) is widely recognized as a fundamental force of genome evolution in prokaryotes. Its importance in multicellular eukaryotes has been disputed and is thought to largely be restricted to transfers from intracellular bacteria and viruses or of mobile DNA. Surprisingly, we uncover a robust phylogenetic signal of HGT from other metazoans within the fungus gnats (family Sciaridae, order Diptera). Up to 12% of the protein-coding genes in the annotation of the model sciarid species Bradysia coprophila are of potential HGT origin. The majority of these genes have phylogenetic affinity with other distantly-related arthropods sharing a similar ecological niche. Using a combination of evolutionary conservation, RNA-Seq, GC content, and codon usage analysis, we provide strong evidence that these HGTs are bona fide genes within the B. coprophila genome, and not the results of genome contamination. In silico ontology and pathway analyses suggest that these HGTs have endowed sciarids with novel biosynthetic and catabolic abilities potentially supportive of their ecological niche as decomposers. Ongoing population genetic and experimental metabolomic analysis seeks to elucidate the selective pressures operating on these genes and confirm their predicted biochemical activities.
1:40PM - 7) Tim Coorens : Getz lab
- Title: Somatic evolution and the origins of cancer and disease
- Summary: From fertilization onwards, the cells of the human body continuously experience damage to their genome, either from intrinsic causes or from exposure to mutagens, which leads to a steady accumulation of somatic mutations. While most somatic mutations are functionally neutral, some can profoundly alter the phenotype of a cell and grant the cell a selective advantage. As we age, our tissues become patchworks of mutant clones, many with canonically cancer- or disease-associated mutations. In this talk, I will summarize my research on the patterns of somatic mutations across normal tissues, the use of mutations as intrinsic barcodes to retrace human and disease development, and the surprising differences in mutation rate and mutational processes active across organs. I will discuss how both cancer and non-cancer diseases are caused by somatic mutations or exert a selection pressure in favor of somatic clones that are able to escape disease toxicity. Taken together, my talk will focus on the origins, patterns and consequences of somatic mutations in human tissues and their roles in health, aging and disease.
2:00PM - 8) Ava Carter and Janet Song : Greenberg and Walsh Labs
- Title: Using human-chimp tetraploid neurons to identify species-specific responses to neuronal activity
- Summary: Compared to other mammals, humans have evolved dramatic modifications to brain morphology and connectivity that likely underlie our unique cognitive abilities. One major modification is a protracted developmental period during which neuronal activity drives an activity-dependent (AD) transcriptional program to contribute to circuit refinement. To identify human-specific genetic variants that underlie changes in the response to neuronal activity, we used a human-chimpanzee tetraploid cell model to measure gene expression and chromatin accessibility differences in excitatory neurons with and without neuronal stimulation. By placing the human and chimpanzee genomes within the same cellular environment, tetraploid cells allow us to disentangle cis-regulated genes, which change in expression due to nearby sequence variants on the same DNA molecule, from trans-regulated genes, which change in expression due to changes in diffusible factors in the cellular environment. Using this model, we identified 73 genes and 1710 non-coding sites that are AD and differentially cis-regulated between human and chimpanzee alleles using RNA-seq and ATAC-seq respectively. Non-coding sites that are AD and differentially cis-regulated are enriched for AP1 motifs, which are bound by FOS, a canonical AD transcription factor. We profiled FOS binding using CUT&Tag and found that ~50% of FOS binding sites show binding that is significantly biased toward human or chimpanzee alleles. Sites that are differentially bound between species are enriched for SNPs within AP1 motifs, as well as in motifs for cooperating transcription factors, suggesting that these sequence changes may be responsible for changes in nearby AD gene expression. Further, we found that targeting the promoters or nearby enhancers for a subset of human-specific AD genes significantly reduces spontaneous neuronal activity as measured on multielectrode arrays. Taken together, our results suggest that genetic variants that arose during human evolution underlie changes to activity-dependent transcription and may alter neuronal function.
2:20PM - 9) David Peede : Huerta-Sánchez lab
- Title: The MUC19 gene in Denisovans, Neanderthals, and Modern Humans: An Evolutionary History of Recurrent Introgression and Natural Selection
- Summary: All humans carry a small fraction of archaic ancestry across the genome, the legacy of interbreeding events with Neanderthals and Denisovans. While the effects of Neanderthal ancestry on human fitness have been thoroughly explored, there are fewer examples of adaptive introgression from Denisovans. Here, we propose a candidate gene for adaptive introgression, MUC19, for which some modern humans carry the Denisovan-like haplotype. MUC19 encodes a member of the gel-forming mucin protein family related to lacrimal and salivary gland function in humans and has been previously proposed as a top candidate for positive selection in Indigenous American populations. We find the Denisovan-like haplotype of MUC19 at its highest frequency in admixed American individuals. Interestingly, the sequenced Denisovan harbors nine missense variants in this region, all of which are fixed in modern-day individuals harboring the introgressed Denisovan-like haplotype. Notably, we find these Denisovan-specific missense variants at high frequencies in admixed individuals from the Americas among global populations and at the highest frequencies in 23 ancient Indigenous American individuals. After conducting allele frequency and haplotype-based tests of selection, we find that the Denisovan-like haplotype of MUC19 is responsible for the signals of positive selection in admixed American populations. Furthermore, two of the three high-coverage Neanderthals carry exactly one Denisovan-like haplotype that modern humans inherited through Neanderthal introgression. Finally, the introgressed MUC19 haplotype carries a higher copy number of a 30 base pair variable number tandem repeat, that copy number variation of this repeat is at high frequency in admixed Latin American populations, and is associated with the number of introgressed haplotypes within an individual at MUC19. Our results suggest a complex pattern of multiple introgression events throughout human history at this locus, first from Denisovans into late Neanderthals, followed by Neanderthal introgression into modern humans, and then selection for the introgressed haplotype in the Americas, which may have played a unique role in the evolutionary history of Indigenous American populations.
2:40PM - 10) Patrick McKenzie : Hopkins lab
- Title: Uncovering the history of a Phlox floral color intensity locus under differential selection
- Summary: We have used association testing and functional research to identify a SNP underlying the change in floral color intensity of Phlox drummondii flowers between light and dark. This trait is expected to be under strong selection due to reinforcement. However, using targeted long-read sequencing, we find that this region lacks characteristic signatures expected from a selective sweep. We leverage population-scale RAD-seq data to infer historical demographic parameters, and we pair these results with forward-time population genomic simulations using SLiM to narrow down the conditions under which variation at this locus could have evolved. By highlighting a parameter space in which classic population genetic scans for selection fail, this work demonstrates the continued relevance of highly targeted research for identifying loci under selection.
3:00PM - 11) Aoxing Liu : Daly lab
- Title: Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection
- Summary: Mosaic loss of the X chromosome (mLOX) is the most commonly occurring clonal somatic alteration detected in the leukocytes of women, yet little is known about its genetic determinants or phenotypic consequences. To address this, we estimated mLOX in > 880,000 women across eight biobanks, identifying 12% of women with detectable X loss in approximately 2% of their leukocytes. Out of 1,253 diseases examined, women with mLOX had an elevated risk of myeloid and lymphoid leukemias. Genetic analyses identified 56 common variants influencing mLOX, implicating genes with established roles in chromosomal missegregation, cancer predisposition, and autoimmune diseases. A small fraction of these associations were shared with mosaic Y chromosome loss in men, suggesting different biological processes drive the formation and clonal expansion of sex chromosome missegregation events. Allelic shift analyses identified alleles on the X chromosome which are preferentially retained, demonstrating that variation at many loci across the X chromosome is under cellular selection. A novel polygenic score including 44 independent X chromosome allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Collectively our results support a model where germline variants predispose women to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of subsequent clonal expansion.
3:20PM - Closing Remarks [Organizers]