About

Andy Clark is a professor in the Department of Molecular Biology & Genetics at Cornell University. His research focuses on molecular biology, genetics, and evolutionary biology, with particular interest in the dynamics of genetic elements such as transposable elements, and their role in development and evolution. The page does not provide detailed information about his specific research projects or background, but it indicates his affiliation and contact information within the department.

Research topics

• Biology
• Genetics
• Computational biology
• Medicine
• Evolutionary biology
• Computer Science
• Internal medicine
• Virology
• Chemistry
• Ecology
• Geography
• Environmental health
• Endocrinology
• Physiology
• Astronomy
• Zoology

Selected publications

• Asymmetric development and function of paired sperm-storage organs in <i>Drosophila melanogaster</i>

  Proceedings of the National Academy of Sciences · 2025-08-19

  articleOpen accessCorresponding

  Paired structures often have similar forms and functions, but the processes underlying their formation can differ. They may originate from a common source or from parallel sources, or arise from distinct precursors that follow separate developmental pathways, ultimately converging on comparable structures and roles. When asymmetries emerge and persist through development, members of the pair can specialize in ways that might increase fitness. Here, we report that the Drosophila melanogaster female’s pair of spermathecae, which appear similar and have the common role of sperm storage, derive from different developmental compartments defined by expression of lineage-tracing markers corresponding, respectively, to the key patterning genes engrailed and wingless . We further find that the two spermathecae show significant differences in size, secretory activity, and calcium levels and, perhaps as a consequence, sperm retention dynamics. These results open broad avenues for understanding how developmental, physiological, and behavioral asymmetries arise and impact reproductive success.

  PublisherDOI

• Addition of thiotepa to a busulphan based conditioning regimen does not improve survival in patients allografted for acute myeloid leukaemia and myelodysplasia: Results of the UK impact cosi trial

  Blood · 2025-11-03 · 1 citations

  articleOpen access

  Abstract Purpose:Disease relapse remains the major cause of treatment failure in patients allografted for acute myeloid leukaemia (AML) and myelodysplasia (MDS). Accumulating data confirms an important contribution of the conditioning regimen to both disease control and transplant toxicity. Thiotepa (Thio) is an alkylating agent whose addition to a busulphan (Bu)/fludarabine (Flu) conditioning regimen has been shown in retrospective studies to improve survival in patients transplanted for AML using both matched unrelated and haploidentical donors, consequent upon a reduction in post-transplant relapse. As a result, Flu/Bu/Thio conditioning regimens are increasingly used in patients allografted for high risk AML despite the absence of prospective randomised trials supporting this practice. COSI is the first prospective randomised trial to examine the benefit of adding Thio to a Flu/Bu based myeloablative (MAC) or reduced intensity (RIC) conditioning regimen in patients allografted for AML in CR1 or CR2 or IPSS high risk MDS. Patients and methods:Three hundred and seventeen patients with high risk AML (n= 242: CR1 n=205, CR2 n=37), or MDS (n= 75) were randomly assigned to undergo transplantation from a matched related sibling (n=52) or matched unrelated donor (n=265) using either a Flu/Bu or Flu/Bu/Thio conditioning regimen. Ninety nine patients were transplanted using a MAC regimen (Flu 40 mg/m2 x 4 days, Bu 3.2 mg/kg x 4 days or Flu 50 mg/m2x 3 days, Bu 3.2 mg/kg x 3 days, Thio 5 mg/kg x 2 days) and 218 patients using a RIC regimen (Flu 30 mg/m2 x 5 days, Bu 3.2 mg/kg x 2 days, or Flu 50 mg/m2 x 3 days, Bu 3.2 mg/kg x 2 days, Thio 5 mg/kg x 1 day). All patients received ciclosporin/ATG-based GVHD prophylaxis. The primary endpoint was overall survival (OS). Results will be presented separately for the MAC (Randomisation 2) and RIC (Randomisation 3) arms of COSI, analysed on intent-to-treat basis analyses, adjusted for stratification factors where possible. The median age of the patients randomised to the MAC arm was 44 years (range 20-54 years) for the RIC arm was 64 (range 31-75 years). Pre-transplant measurable residual disease (MRD) was measured 28 days prior to transplant by flow cytometry (MFC-MRD) and correlated with outcome in both the MAC and RIC arms, using an MRD threshold of 0.1%. Results:In the 99 patients randomised to the MAC arm, addition of Thio to a Flu/Bu4 conditioning regimen did not increase 2 year OS: 75% using Flu/Bu4 versus 72% using Flu/Bu3/Thio (p=0.73). In patients who were MRD negative pre-transplant 2 year OS in patients transplanted using Flu/Bu4 was 81% versus 70% in patients transplanted using Flu/Bu3/Thio (p=0.91). In patients who were MRD positive pre-transplant 2 year OS using Flu/Bu4was 67% versus 63% for patients transplanted using Flu/Bu3/Thio (p=0.55). The 2 year cumulative incidence of relapse (CIR) was lower in patients transplanted using a Flu/Bu4/Thio conditioning regimen: 11% using Flu/Bu4/Thio versus 31% using Flu/Bu4 (p=&amp;lt;0.001). However, in contrast the 2-year transplant-related mortality (TRM) in patients transplanted using a Flu/Bu4/Thio regimen was increased: 22% using Flu/Bu4/Thio versus 4% using Flu/Bu4 (p=&amp;lt;0.001). In the 218 patients randomised to the RIC arm the addition of Thio did not increase 2 year OS: 71% using Flu/Bu2versus 69% using Flu/Bu2/Thio (p=0.87). In patients who were MRD negative pre-transplant 2 year OS was 84% using Flu/Bu2versus 75% for patients transplanted using Flu/Bu2/Thio (p=0.45). In patients who were MRD positive pre-transplant 2 year OS was 56% using Flu/Bu2/Thio versus 41% in patients transplanted using Flu/Bu2 (p=0.15). The 2 year TRM in patients transplanted using a Flu/Bu2/Thio regimen was increased: 17% using Flu/Bu2/Thio versus 8% using Flu/Bu2 (p=0.01). The 2 year CIR in patients transplanted using a Flu/Bu2/Thio regimen was 20% versus 30% in patients transplanted using a Flu/Bu2 regimen (p=0.12). Conclusion:This prospective randomised trial demonstrates that the addition of Thio to either a Flu/Bu based MAC or RIC regimen does not improve survival in patients allografted for AML or MDS and was associated with an increased TRM in both settings. Further prospective studies examining the ability of Thio to reduce the risk of disease relapse in high risk patients whilst at the same time limiting transplant toxicity are merited.

  PublisherOA PDFDOI

• Comparative population genomics reveals adaptive convergence in two <i>Drosophila</i> species across global environments

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-03 · 1 citations

  preprintOpen access

  Abstract The extent to which evolution is predictable across lineages remains unclear. To address this question, we investigated convergent adaptation in a pair of globally distributed sibling species, Drosophila melanogaster and D. simulans . We integrated whole-genome data from approximately 2,000 strains sampled across major continents, and revealed a more recent global colonization of D. simulans relative to D. melanogaster . Using a suite of complementary selection scans, we quantified signatures of positive selection across evolutionary timescales and genomic contexts. Despite substantial divergence, approximately 9–13% of adaptively evolving genes were shared between species across methods, revealing widespread convergence at the gene and pathway levels. Convergence was particularly pronounced for insecticide resistance genes, and was also evident in oxidative stress experiment. This study provides a quantitative, multiscale framework for dissecting molecular convergence, offering insights into the predictability of evolution, the constraints imposed by genomic architecture, and the dynamics of adaptation under global environmental change.

  PublisherOA PDFDOI

• Longitudinal sequencing reveals polygenic and epistatic nature of genomic response to selection

  Proceedings of the National Academy of Sciences · 2025-06-18 · 3 citations

  articleOpen accessCorresponding

  Evolutionary adaptation to new environments likely results from a combination of selective sweeps and polygenic shifts, depending on the genetic architecture of traits under selection. While selective sweeps have been widely studied, polygenic responses are thought to be more prevalent but remain challenging to quantify. The infinitesimal model makes explicit the hypothesis about the dynamics of changes in allele frequencies under selection, where only allelic effect sizes, frequencies, linkage, and gametic disequilibrium matter. Departures from this, like long-range correlations of allele frequency changes, could be a signal of epistasis in polygenic response. We performed an Evolve &amp; Resequence experiment in Drosophila melanogaster exposing flies to a high-sugar diet for over 100 generations. We tracked allele frequency changes in &gt;3000 individually sequenced flies and population pools and searched for loci under selection by identifying sites with allele frequency trajectories that differentiated selection regimes consistently across replicates. We estimate that at least 4% of the genome was under positive selection, indicating a highly polygenic response. The response was dominated by small, consistent allele frequency changes, with few loci exhibiting large shifts. We then searched for signatures of selection on pairwise combinations of alleles in the new environment and found several strong signals of putative epistatic interactions across unlinked loci that were consistent across selected populations. Finally, we measured differentially expressed genes (DEGs) across treatments and show that DEGs are enriched for selected SNPs. Our results suggest that epistatic contributions to polygenic selective response are common and lead to detectable signatures.

  PublisherOA PDFDOI

• The <i>Stellate</i> meiotic drive system of <i>Drosophila melanogaster</i> is active in contemporary populations

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-04 · 2 citations

  preprintOpen accessSenior author

  Abstract Meiotic drivers are selfish elements that bias their own transmission so that they are overrepresented among the functional gametes produced. The selective costs imposed by drivers on their hosts may trigger intragenomic conflict, promoting the evolution of suppressors and fueling an ongoing arms race between drivers and suppressors. Stellate ( Ste ) is an X-linked tandemly arrayed multicopy gene. Its copy number ranges from 3 to more than 300 among Drosophila melanogaster strains from the Global Diversity Lines. In wild-type animals, Ste expression is usually suppressed by homologous piRNAs produced from the Suppressor of Stellate ( Su(Ste) ) array on the Y chromosome. Derepression of Ste in the absence of Su(Ste) results in the formation of proteinaceous crystals in spermatocytes, chromatin compaction defects, reductions in fertility, and female-biased sex ratios arising from under-recovery of Y-bearing sperm. Despite extensive study, the function of the Stellate array and evolutionary significance of its persistence in the genome have remained elusive. It has been suggested to be a now-inactive relic of an ancient meiotic drive system, as perturbations in lab stocks can produce Ste -mediated meiotic distortions. Meiotic drive occurring among natural variants, however, has not been reported. We established crosses between females with high Ste copy number X chromosomes and males carrying low Su(Ste) copy number Y chromosomes and found that the male progeny displayed non-Mendelian sex chromosome transmission. Importantly, deletion of the euSte array in an otherwise matched genetic background rescues this phenotype, demonstrating that Stellate is an active driver in contemporary populations.

  PublisherOA PDFDOI

• Whole-Genome Sequencing Across Space and Time Reveals Impact of Population Decline and Reduced Gene Flow in Florida Scrub-Jays

  SSRN Electronic Journal · 2025-01-01

  preprintOpen accessSenior author
  PublisherDOI

• AAV delivery of full-length SYNGAP1 rescues epileptic and behavioral phenotypes in a mouse model of SYNGAP1-related disorders

  Molecular Therapy · 2025-09-24 · 8 citations

  articleOpen access
  PublisherOA PDFDOI

• Bayesian phylodynamic inference of population dynamics with dormancy

  Proceedings of the National Academy of Sciences · 2025-05-02

  articleOpen accessCorresponding

  Many organisms employ reversible dormancy, or seedbank, in response to environmental fluctuations. This life-history strategy alters fundamental ecoevolutionary forces, leading to distinct patterns of genetic diversity. Two models of dormancy have been proposed based on the average duration of dormancy relative to coalescent timescales: weak seedbank, induced by scheduled seasonality (e.g., plants, invertebrates), and strong seedbank, where individuals stochastically switch between active and dormant states (e.g., bacteria, fungi). The weak seedbank coalescent is statistically equivalent to the Kingman coalescent with a scaled mutation rate, allowing the use of existing inference methods. In contrast, the strong seedbank coalescent differs fundamentally, as only active lineages can coalesce, while dormant lineages cannot. Additionally, dormant individuals typically mutate at a slower rate than active ones. Consequently, despite the significant role of dormancy in the ecoevolutionary dynamics of many organisms, no methods currently exist for inferring population dynamics involving dormancy and associated parameters. We present a Bayesian framework for jointly inferring a latent genealogy, seedbank parameters, and evolutionary parameters from molecular sequence data under the strong seedbank coalescent. We derive the exact probability density of genealogies sampled under the strong seedbank coalescent, characterize the corresponding likelihood function, and present efficient computational algorithms for its evaluation based on our theoretical framework. We develop a tailored Markov chain Monte Carlo sampler and implement our inference framework as a package SeedbankTree within BEAST2. Our work provides both a theoretical foundation and practical inference framework for studying the population genetic and genealogical impacts of dormancy.

  PublisherOA PDFDOI

• Pervasive sex-dependent effects in the genetic architecture of starvation resistance in <i>Drosophila melanogaster</i>

  Science Advances · 2025-09-26 · 2 citations

  articleOpen access

  Genetic variants can have sex-specific, sex-biased, or sexually antagonistic fitness effects, yet their roles in fitness-related traits remain unclear. Using pooled phenotype sorting and sequencing of male Drosophila melanogaster from natural populations, we identified starvation resistance–associated variants, many in regulatory regions or altering protein sequences. RNA interference experiments showed that 85.7% (66 of 77) of the candidate genes with nonlethal knockdown effects influenced starvation resistance. Of these, 49 had sex-dependent effects, including 12 with sexually antagonistic effects—all increasing resistance in females but decreasing it in males. These patterns were not explained by sex-biased expression or knockdown efficiency. Analysis of the Lnk gene revealed that both nonsynonymous mutations and expression changes had sex-dependent effects. Our findings indicate that polygenic architecture, sex-dependent effects, and pleiotropy jointly shape evolutionary outcomes and that some variants maintained by these forces may enable rapid responses to environmental change.

  PublisherDOI

• Subcellular Enrichment Patterns of New Genes in <i>Drosophila</i> Evolution

  Molecular Biology and Evolution · 2025-02-01 · 4 citations

  articleOpen access

  The evolutionary patterns of proteins within subcellular compartments underlie the innovation and diversification foundation of the living eukaryotic organism. The location of proteins in subcellular compartments promotes the formation of network interaction modules, which in turn reshape the architecture of higher-level protein-protein interaction networks. Here, we conducted the most up-to-date gene age dating of Drosophila melanogaster by employing recently available long-read sequencing genomes as references. We found that an elevated gene fixation in the most recent common ancestor of Drosophila genus predated the divergence between two Drosophila subgenera, and a significant tendency of these genes in D. melanogaster encode proteins that localize to the extracellular matrix, accompanying the adaptive radiation of Drosophila species. Proteins encoded by genes located in the extracellular space exhibit higher sequence divergence, suggesting a rapid evolutionary process. We also observed that proteins encoded by genes originating from the same evolutionary branches tend to co-localize in the same subcellular compartments, and proteins in the same subcellular compartment tend to interact with each other. The proteins encoded by genes that have persisted through deeper branches exhibit broader localization across multiple subcellular compartments, enhancing the likelihood of their integration into various protein or gene regulatory networks, thereby increasing functional diversity. These evolutionary patterns not only contribute to understanding the evolution of subcellular localization in proteins encoded by genes originating from different branches, but also provide insights into the evolution of protein-protein networks driven by the emergence of new genes.

  PublisherDOI

Recent grants

• NIH Grant R01HD021963

  NIH · $202k · 1991

• Genetic Transmission of Componenets of the Human Gut Microbiome

  NIH · $3.5M · 2011–2023

• NIH Grant U01HG005715

  NIH · $1.1M · 2014

• REGULATION OF GAMETE USE AND NEURAL PATHWAYS IN REPRODUCTION

  NIH · $5.8M · 2009–2027

• Reference-quality Drosophila genome assemblies for evolutionary analysis of previously inaccessible genomic regions

  NIH · $1.7M · 2016–2022

Frequent coauthors

• Richard A. Gibbs

  Baylor College of Medicine

  96 shared

• Carlos D. Bustamante

  72 shared

• Jackson Champer

  Peking University

  60 shared

• Laura Clarke

  New York Genome Center

  59 shared

• Donna M. Muzny

  58 shared

• Gil McVean

  University of Oxford

  57 shared

• Andrew R. Marderstein

  Stanford University

  57 shared

• Charles Lee

  University of California, San Francisco

  56 shared

Labs

• Clark Lab at CornellPI

Awards & honors

• Elected to 2012 National Academy of Sciences
• Honorary Doctorate 2009 Oulu University, Finland
• Fellow 2000 American Association for the Advancement of Scie…
• Study Section Member 1997 NIH NATO and Marshall Postdoctoral…