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Bell, Avery

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Bell

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Avery

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Bell, Avery

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2016 - 20192

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Author's Publications: search.filters.isAuthorOfPublication.b5ce42d8-17a7-4028-8cf0-381d8d08ba6f

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    Insights about variation in meiosis from 31,228 human sperm genomes
    (Springer Nature, 2019-05-02) Bell, Avery; Mello, Curtis; Nemesh, James; Brumbaugh, Sara A; Wysoker, Alec; McCarroll, Steven
    Meiosis, while critical for reproduction, is also variable and error-prone: crossover rates vary among gametes, between the sexes, and among humans of the same sex, and chromosome mis-segregation leads to aneuploidy1-8. To study diverse meiotic outcomes and how they co-vary across chromosomes, gametes, and humans, we developed Sperm-seq, a way to simultaneously sequence the genomes of thousands of individual sperm. We analyzed the genomes of 31,228 human gametes from 20 sperm donors, identifying 813,122 crossovers and 787 aneuploid chromosomes. Sperm donors had aneuploidy rates ranging from 0.01 to 0.05 aneuploidies per gamete; crossovers partially protected chromosomes from nondisjunction at meiosis I. Some chromosomes and donors underwent more-frequent non-disjunction during the meiosis I cell division, while other chromosomes and donors showed more segregation failures during meiosis II; many genomic anomalies that could not be explained by simple nondisjunction also occurred. Diverse recombination phenotypes – from crossover rates to crossover location and separation (a measure of crossover interference) – co-varied strongly across individuals and cells. Our results can be incorporated with earlier observations into a unified model in which a core mechanism – the variable physical compaction of meiotic chromosomes – generates inter-individual and cell-to-cell variation in diverse meiotic phenotypes.
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    Schizophrenia risk from complex variation of complement component 4
    (2016) Sekar, Aswin; Rosen, Allison; de Rivera, Heather; Bell, Avery; Hammond, Timothy; Kamitaki, Nolan; Tooley, Katherine; Presumey, Jessy; Baum, Matt; Van Doren, Vanessa; Genovese, Giulio; Rose, Samuel A.; Handsaker, Robert; Daly, Mark; Carroll, Michael C.; Stevens, Beth; McCarroll, Steven
    Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the Major Histocompatibility Complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to recognize. We show here that schizophrenia’s association with the MHC locus arises in substantial part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles promoted widely varying levels of C4A and C4B expression and associated with schizophrenia in proportion to their tendency to promote greater expression of C4A in the brain. Human C4 protein localized at neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals affected with schizophrenia.