Annual Retreat 2022

Monadnock Room (2nd fl), Merkin Building, Broad Institute (415 Main Street, Cambridge, MA 02142) - Registration is required

8:50AM - Breakfast

9:10AM - Welcome/Introduction [Organizers]

9:20AM - *Keynote Speaker : Janet Kelso, MPG*

:: Research Group Leader: Computational Ancient Genomics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany ::

  • Title: Human evolution in the light of introgression
  • Summary: Comparison of the genome sequences of Neandertals and Denisovans to those of modern humans has provided a unique window into their shared histories, revealing that gene flow between archaic and modern humans has occurred at multiple times and in multiple directions.  The replacement of Neandertals by modern humans around 35-45kya was accompanied by gene flow such that Neandertal ancestry is found in all descendants outside sub-Saharan Africa. In addition, archaeological discoveries such as Apidima 1 in Greece, suggest that modern humans also migrated from Africa to southern Europe even earlier, and we think that based on patterns of relatedness among hominin mitochondrial and Y chromosomes that they may also have mixed with archaic humans at that time. My group has been interested in how the presence and proportion of introgressed DNA, as well as the timing of introgression can be used to learn about the history of archaic and modern human populations. We have also explored the genomic distribution and frequency of introgressed DNA fragments to understand how selection has operated on introgressed DNA and what this tells us about traits that have been important in modern human history.

10:30AM - Coffee Break (30min)

11:00AM - 1) Idan Frumkin: Michael Laub lab

  • Title: Random Proteins provide Evolutionary Novelty by assuming Diverse Cellular Functions
  • Summary: How do organisms evolve new functions? While novelty usually emerges by modifying existing genes, novo gene birth is another mechanism in which short open reading frames originate from random sequences. However, it is poorly understood what functions such de novo proteins serve and how they integrate into complex cellular systems. To investigate whether proteins with random sequences can benefit cells, we screened a library of ~5x108 random proteins, with no homology to existing proteins, for the ability to promote survival of Escherichia coli cells facing two threats: (i) the toxin MazF or (ii) the bacteriophage T4. We found ~2000 random proteins that inhibit MazF and characterized the mechanism of one of them. This random protein integrates into central protein homeostasis pathways, leading to rapid degradation of MazF and survival of cells. Additionally, we found several random proteins that inhibit T4 phage infection by preventing viral entry into cells through mechanisms such as modifying the bacterial outer-membrane or decreasing protein levels of the phage receptor protein. Our work demonstrates that random proteins can easily integrate into existing cellular systems with minimal burden to promote bacterial survival via distinct molecular mechanisms, and thus serve as a rich source for functional novelty.

11:20AM - 2) Alief Moulana / Thomas Dupic: Michael Desai lab 

  • Title:  Compensatory epistasis maintains ACE2 affinity in Omicron BA.1 variant
  • Summary: The Omicron BA.1 variant emerged in late 2021 and quickly spread across the world. Compared to the ancestral Wuhan Hu-1 strain and other pre-Omicron SARS-CoV-2 variants, BA.1 has many mutations, a number of which are known to enable antibody escape. Many of these antibody-escape mutations individually decrease the spike receptor-binding domain (RBD) affinity for ACE2 in the background of early SARS-CoV-2 variants, but BA.1 still binds ACE2 with high affinity. The fitness and evolution of the BA.1 lineage is therefore driven by the combined effects of numerous mutations. Here, we systematically map the epistatic interactions between the 15 mutations in the RBD of BA.1 relative to the Wuhan Hu-1 strain. Specifically, we measure the ACE2 affinity of all possible combinations of these 15 mutations (215 = 32,768 genotypes), spanning all possible evolutionary intermediates from the ancestral Wuhan Hu-1 strain to BA.1. We find that immune escape mutations in BA.1 individually reduce ACE2 affinity but are compensated by epistatic interactions with other affinity-enhancing mutations, including Q498R and N501Y. Thus, the ability of BA.1 to evade immunity while maintaining ACE2 affinity is contingent on acquiring multiple interacting mutations. Our results implicate compensatory epistasis as a key factor driving substantial evolutionary change for SARS-CoV-2 and are consistent with Omicron BA.1 arising from a chronic infection.

11:40AM - 3) Bo Xia: Bo Xia lab

  • Title:  Genetic basis of hominoid-specific evolution: tail-loss and beyond
  • Summary: Hominoids, including modern human, shares many anatomical and developmental features defining their behaviors. Among those, the loss of the tail is one of the main anatomical changes to have occurred along the lineage of hominoids. This morphological reprogramming in the ancestral hominoids has been long considered to have accommodated a characteristic style of locomotion and contributed to the evolution of bipedalism in humans. Yet, the precise genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Primate genome sequencing projects have made possible the identification of causal links between genotypic and phenotypic changes. In particular, a comparative genomics approach can screen for hominoid-specific genetic elements in genomic regions associated with genes and their regulatory circuits known to be involved in controlling development. Here, we present evidence that tail-loss evolution was mediated by the insertion of an individual transposable element (TE) ‚ Alu element ‚ into the intron of the TBXT gene (also called T or Brachyury) of the hominoid ancestor genome. We demonstrated that, unlike traditional TE insertion which typically acts by itself, this Alu element in TBXT forms an interaction pair with another ancestral Alu element,  thus inducing a hominoid-specific TBXT alternative splicing and ultimately influencing tail development and evolution. We further propose that selection for the loss of the tail along the hominoid lineage might be associated with an adaptive cost of potential neural tube defect as an evolutionary trade-off, which may thus continue to affect human health today.

12:00PM - Lunch 

1:00PM - 4) Gautam Reddy: Michael Desai lab

  • Title:  Inferring sparse structure from genotype-phenotype maps
  • Summary: The architecture of the genotype-phenotype map critically determines evolutionary trade-offs and adaptive paths available to an organism. Covariation patterns in genotype-phenotype data offer the potential to identify phenotype-determining core processes influenced by common collections of genes. However, unique identification of these latent processes is infeasible without additional biologically-motivated constraints. We show that the genotype-phenotype map is sparse across datasets, and that a sparsity-favoring matrix decomposition approach can accurately recover latent processes if each genetic perturbation affects few core processes or if each phenotype is affected by few core processes. We develop a matrix decomposition framework for sparse structure discovery (SSD). We demonstrate broad applicability of our method on three empirical datasets spanning natural variation from a yeast cross, adaptive mutations in yeast and a genotoxin robustness assay in human cell lines. More generally, we propose sparsity as a guiding prior for resolving latent structure from empirical genotype-phenotype maps.

1:20PM - 5) Samuel Arsenault: Waring Trible Lab

  • Title:  Queen polymorphism in Leptothorax ergatogyneous: its morphological and genetic background
  • Summary: Ants within the Leptothorax genus group exhibit tremendous natural history diversity, and this variation is accompanied by variation in morphological caste phenotypes. While some species exhibit a canonical caste syndrome with wingless workers and winged queens, others, like Leptothorax ergatogyneous, possess a Mendelian genetic polymorphism for both winged queens and wingless ergatoid queens. The natural diversity of this clade of ants provides an opportunity to identify molecular mechanisms underlying caste development and the evolution of novel caste morphologies. Here we will describe our initial efforts to quantify the morphological variation within and between castes in Leptothorax ergatogyneous. Additionally, we describe the generation of a new reference genome and large-scale resequencing dataset that will enable us to identify and characterize the Mendelian element that induces the development of wingless queens. This represents the first identification of a genetic caste polymorphism in a natural population and could yield novel insights into the molecular mechanisms of ant caste development.

1:40PM - 6) Ali Akbari: David Reich lab

  • Title:  Evolutionary history of genetic variants and polygenic adaptation in Western Eurasia using aDNA time series
  • Summary: Since the release of the first draft of the human genome many useful resources have become available to trace the genetic footprint of natural selection using present-day people. However, admixture and population structure, varying mutation and recombination rate across the genome, bottleneck and effective population size variation, presence of structural variants, and other factors can create spurious signal of selection and make it challenging to estimate the origin time and location of the evolution using a snapshot of the modern human populations. Correcting for all these confounders has always been challenging in population genetic studies. Using time series approaches in a controlled environment (evolve and resequencing) to better understand the evolutionary history of model organisms is a highly powerful approach, but it is impossible to run a time series experiment for humans. However, with the rise of ancient DNA sample sizes we have a natural time series data of human genomes that can dramatically improve the resolution of evolutionary studies. In this study, we developed an unsupervised approach using aDNA time series to study Natural selection and polygenic adaptation in ~6000 Western Eurasian individuals in the past 12,000 years ago.     

2:00PM - Closing Remarks [Organizers]