All Publications

  • A rarefaction approach for measuring population differences in rare and common variation. Genetics Cotter, D. J., Hofgard, E. F., Novembre, J., Szpiech, Z. A., Rosenberg, N. A. 2023


    In studying allele-frequency variation across populations, it is often convenient to classify an allelic type as "rare," with nonzero frequency less than or equal to a specified threshold, "common," with frequency above the threshold, or entirely unobserved in a population. When sample sizes differ across populations, however, especially if the threshold separating "rare" and "common" corresponds to a small number of observed copies of an allelic type, discreteness effects can lead a sample from one population to possess substantially more rare allelic types than a sample from another population, even if the two populations have extremely similar underlying allele-frequency distributions across loci. We introduce a rarefaction-based sample-size correction for use in comparing rare and common variation across multiple populations whose sample sizes potentially differ. We use our approach to examine rare and common variation in worldwide human populations, finding that the sample-size correction introduces subtle differences relative to analyses that use the full available sample sizes. We introduce several ways in which the rarefaction approach can be applied: we explore dependence of allele classifications on subsample sizes, we permit more than two classes of allelic types of nonzero frequency, and we analyze rare and common variation in sliding windows along the genome. The results can assist in clarifying similarities and differences in allele-frequency patterns across populations.

    View details for DOI 10.1093/genetics/iyad070

    View details for PubMedID 37075098

  • Limiting distribution of X-chromosomal coalescence times under first-cousin consanguineous mating. Theoretical population biology Cotter, D. J., Severson, A. L., Carmi, S., Rosenberg, N. A. 2022


    By providing additional opportunities for coalescence within families, the presence of consanguineous unions in a population reduces coalescence times relative to non-consanguineous populations. First-cousin consanguinity can take one of six forms differing in the configuration of sexes in the pedigree of the male and female cousins who join in a consanguineous union: patrilateral parallel, patrilateral cross, matrilateral parallel, matrilateral cross, bilateral parallel, and bilateral cross. Considering populations with each of the six types of first-cousin consanguinity individually and a population with a mixture of the four unilateral types, we examine coalescent models of consanguinity. We previously computed, for first-cousin consanguinity models, the mean coalescence time for X-chromosomal loci and the limiting distribution of coalescence times for autosomal loci. Here, we use the separation-of-time-scales approach to obtain the limiting distribution of coalescence times for X-chromosomal loci. This limiting distribution has an instantaneous coalescence probability that depends on the probability that a union is consanguineous; lineages that do not coalesce instantaneously coalesce according to an exponential distribution. We study the effects on the coalescence time distribution of the type of first-cousin consanguinity, showing that patrilateral-parallel and patrilateral-cross consanguinity have no effect on X-chromosomal coalescence time distributions and that matrilateral-parallel consanguinity decreases coalescence times to a greater extent than does matrilateral-cross consanguinity.

    View details for DOI 10.1016/j.tpb.2022.07.002

    View details for PubMedID 35973448

  • The effect of consanguinity on coalescence times on the X chromosome. Theoretical population biology Cotter, D. J., Severson, A. L., Rosenberg, N. A. 2021


    Consanguineous unions increase the frequency at which identical genomic segments are inherited along separate paths of descent, decreasing coalescence times for pairs of alleles drawn from an individual who is the offspring of a consanguineous pair. For an autosomal locus, it has recently been shown that the mean time to the most recent common ancestor (TMRCA) for two alleles in the same individual and the mean TMRCA for two alleles in two separate individuals both decrease with increasing consanguinity in a population. Here, we extend this analysis to the X chromosome, considering X-chromosomal coalescence times under a coalescent model with diploid, male-female mating pairs. We examine four possible first-cousin mating schemes that are equivalent in their effects on autosomes, but that have differing effects on the X chromosome: patrilateral-parallel, patrilateral-cross, matrilateral-parallel, and matrilateral-cross. In each mating model, we calculate mean TMRCA for X-chromosomal alleles sampled either within or between individuals. We describe a consanguinity effect on X-chromosomal TMRCA that differs from the autosomal pattern under matrilateral but not under patrilateral first-cousin mating. For matrilateral first cousins, the effect of consanguinity in reducing TMRCA is stronger on the X chromosome than on the autosomes, with an increased effect of parallel-cousin mating compared to cross-cousin mating. The theoretical computations support the utility of the model in understanding patterns of genomic sharing on the X chromosome.

    View details for DOI 10.1016/j.tpb.2021.03.004

    View details for PubMedID 33901539

  • The GTEx Consortium atlas of genetic regulatory effects across human tissues SCIENCE Aguet, F., Barbeira, A. N., Bonazzola, R., Brown, A., Castel, S. E., Jo, B., Kasela, S., Kim-Hellmuth, S., Liang, Y., Parsana, P., Flynn, E., Fresard, L., Gamazon, E. R., Hamel, A. R., He, Y., Hormozdiari, F., Mohammadi, P., Munoz-Aguirre, M., Ardlie, K. G., Battle, A., Bonazzola, R., Brown, C. D., Cox, N., Dermitzakis, E. T., Engelhardt, B. E., Garrido-Martin, D., Gay, N. R., Getz, G., Guigo, R., Hamel, A. R., Handsaker, R. E., He, Y., Hoffman, P. J., Hormozdiari, F., Im, H., Jo, B., Kasela, S., Kashin, S., Kim-Hellmuth, S., Kwong, A., Lappalainen, T., Li, X., Liang, Y., MacArthur, D. G., Mohammadi, P., Montgomery, S. B., Munoz-Aguirre, M., Rouhana, J. M., Hormozdiari, F., Im, H., Kim-Hellmuth, S., Ardlie, K. G., Getz, G., Guigo, R., Im, H., Lappalainen, T., Montgomery, S. B., Im, H., Lappalainen, T., Lappalainen, T., Anand, S., Gabriel, S., Getz, G., Graubert, A., Hadley, K., Handsaker, R. E., Huang, K. H., Kashin, S., Li, X., MacArthur, D. G., Meier, S. R., Nedzel, J. L., Balliu, B., Conrad, D., Cotter, D. J., Das, S., de Goede, O. M., Eskin, E., Eulalio, T. Y., Ferraro, N. M., Garrido-Martin, D., Gay, N. R., Getz, G., Graubert, A., Guigo, R., Hadley, K., Hamel, A. R., Handsaker, R. E., He, Y., Hoffman, P. J., Hormozdiari, F., Hou, L., Huang, K. H., Im, H., Jo, B., Kasela, S., Kashin, S., Kellis, M., Kim-Hellmuth, S., Kwong, A., Lappalainen, T., Li, X., Li, X., Liang, Y., MacArthur, D. G., Mangul, S., Meier, S. R., Mohammadi, P., Montgomery, S. B., Munoz-Aguirre, M., Nachun, D. C., Nedzel, J. L., Nguyen, D. Y., Nobel, A. B., Park, Y., Reverter, F., Sabatti, C., Saha, A., Segre, A., Stephens, M., Strober, B. J., Teran, N. A., Todres, E., Vinuela, A., Wang, G., Wen, X., Wright, F., Wucher, V., Zou, Y., Ferreira, P. G., Li, G., Mele, M., Yeger-Lotem, E., Barcus, M. E., Bradbury, D., Krubit, T., McLean, J. A., Qi, L., Robinson, K., Roche, N., Smith, A. M., Tabor, D. E., Undale, A., Bridge, J., Brigham, L. E., Foster, B. A., Gillard, B. M., Hasz, R., Hunter, M., Johns, C., Johnson, M., Karasik, E., Kopen, G., Leinweber, W. F., McDonald, A., Moser, M. T., Myer, K., Ramsey, K. D., Roe, B., Shad, S., Thomas, J. A., Walters, G., Washington, M., Wheeler, J., Jewell, S. D., Rohrer, D. C., Valley, D. R., Davis, D. A., Mash, D. C., Branton, P. A., Sobin, L., Barker, L. K., Gardiner, H. M., Mosavel, M., Siminoff, L. A., Flicek, P., Haeussler, M., Juettemann, T., Kent, W., Lee, C. M., Powell, C. C., Rosenbloom, K. R., Ruffier, M., Sheppard, D., Taylor, K., Trevanion, S. J., Zerbino, D. R., Abell, N. S., Akey, J., Chen, L., Demanelis, K., Doherty, J. A., Feinberg, A. P., Hansen, K. D., Hickey, P. F., Hou, L., Jasmine, F., Jiang, L., Kaul, R., Kellis, M., Kibriya, M. G., Li, J., Li, Q., Lin, S., Linder, S. E., Montgomery, S. B., Oliva, M., Park, Y., Pierce, B. L., Rizzardi, L. F., Skol, A. D., Smith, K. S., Snyder, M., Stamatoyannopoulos, J., Tang, H., Wang, M., Carithers, L. J., Guan, P., Koester, S. E., Little, A., Moore, H. M., Nierras, C. R., Rao, A. K., Vaught, J. B., Volpi, S., GTEx Consortium 2020; 369 (6509): 1318-+
  • The impact of sex on gene expression across human tissues. Science (New York, N.Y.) Oliva, M. n., Muñoz-Aguirre, M. n., Kim-Hellmuth, S. n., Wucher, V. n., Gewirtz, A. D., Cotter, D. J., Parsana, P. n., Kasela, S. n., Balliu, B. n., Viñuela, A. n., Castel, S. E., Mohammadi, P. n., Aguet, F. n., Zou, Y. n., Khramtsova, E. A., Skol, A. D., Garrido-Martín, D. n., Reverter, F. n., Brown, A. n., Evans, P. n., Gamazon, E. R., Payne, A. n., Bonazzola, R. n., Barbeira, A. N., Hamel, A. R., Martinez-Perez, A. n., Soria, J. M., Pierce, B. L., Stephens, M. n., Eskin, E. n., Dermitzakis, E. T., Segrè, A. V., Im, H. K., Engelhardt, B. E., Ardlie, K. G., Montgomery, S. B., Battle, A. J., Lappalainen, T. n., Guigó, R. n., Stranger, B. E. 2020; 369 (6509)


    Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation.

    View details for DOI 10.1126/science.aba3066

    View details for PubMedID 32913072

  • Ancient Rome: A genetic crossroads of Europe and the Mediterranean. Science (New York, N.Y.) Antonio, M. L., Gao, Z. n., Moots, H. M., Lucci, M. n., Candilio, F. n., Sawyer, S. n., Oberreiter, V. n., Calderon, D. n., Devitofranceschi, K. n., Aikens, R. C., Aneli, S. n., Bartoli, F. n., Bedini, A. n., Cheronet, O. n., Cotter, D. J., Fernandes, D. M., Gasperetti, G. n., Grifoni, R. n., Guidi, A. n., La Pastina, F. n., Loreti, E. n., Manacorda, D. n., Matullo, G. n., Morretta, S. n., Nava, A. n., Fiocchi Nicolai, V. n., Nomi, F. n., Pavolini, C. n., Pentiricci, M. n., Pergola, P. n., Piranomonte, M. n., Schmidt, R. n., Spinola, G. n., Sperduti, A. n., Rubini, M. n., Bondioli, L. n., Coppa, A. n., Pinhasi, R. n., Pritchard, J. K. 2019; 366 (6466): 708–14


    Ancient Rome was the capital of an empire of ~70 million inhabitants, but little is known about the genetics of ancient Romans. Here we present 127 genomes from 29 archaeological sites in and around Rome, spanning the past 12,000 years. We observe two major prehistoric ancestry transitions: one with the introduction of farming and another prior to the Iron Age. By the founding of Rome, the genetic composition of the region approximated that of modern Mediterranean populations. During the Imperial period, Rome's population received net immigration from the Near East, followed by an increase in genetic contributions from Europe. These ancestry shifts mirrored the geopolitical affiliations of Rome and were accompanied by marked interindividual diversity, reflecting gene flow from across the Mediterranean, Europe, and North Africa.

    View details for DOI 10.1126/science.aay6826

    View details for PubMedID 31699931

  • Genetic Diversity on the Human X Chromosome Does Not Support a Strict Pseudoautosomal Boundary GENETICS Cotter, D. J., Brotman, S. M., Sayres, M. 2016; 203 (1): 485-+


    Unlike the autosomes, recombination between the X chromosome and the Y chromosome is often thought to be constrained to two small pseudoautosomal regions (PARs) at the tips of each sex chromosome. PAR1 spans the first 2.7 Mb of the proximal arm of the human sex chromosomes, whereas the much smaller PAR2 encompasses the distal 320 kb of the long arm of each sex chromosome. In addition to PAR1 and PAR2, there is a human-specific X-transposed region that was duplicated from the X to the Y chromosome. The X-transposed region is often not excluded from X-specific analyses, unlike the PARs, because it is not thought to routinely recombine. Genetic diversity is expected to be higher in recombining regions than in nonrecombining regions because recombination reduces the effect of linked selection. In this study, we investigated patterns of genetic diversity in noncoding regions across the entire X chromosome of a global sample of 26 unrelated genetic females. We found that genetic diversity in PAR1 is significantly greater than in the nonrecombining regions (nonPARs). However, rather than an abrupt drop in diversity at the pseudoautosomal boundary, there is a gradual reduction in diversity from the recombining through the nonrecombining regions, suggesting that recombination between the human sex chromosomes spans across the currently defined pseudoautosomal boundary. A consequence of recombination spanning this boundary potentially includes increasing the rate of sex-linked disorders (e.g., de la Chapelle) and sex chromosome aneuploidies. In contrast, diversity in PAR2 is not significantly elevated compared to the nonPARs, suggesting that recombination is not obligatory in PAR2. Finally, diversity in the X-transposed region is higher than in the surrounding nonPARs, providing evidence that recombination may occur with some frequency between the X and Y chromosomes in the X-transposed region.

    View details for DOI 10.1534/genetics.114.172692

    View details for Web of Science ID 000376012100032

    View details for PubMedID 27010023

    View details for PubMedCentralID PMC4858793