We propose research which is novel, hypothesis driven, transformative, and relevant to the NIH mission. The novelty emerges from our recent discovery that the Y chromosome of Drosophila melanogaster is polymorphic for sequences that differentially affect the expression of many hundreds of autosomal and X-linked genes. The quantitative effects of different Y chromosome on gene expression are termed YRV (Y-linked regulatory variation). The proposed experiments provide the first molecular approach to study the mechanism of YRV. The genes affected by YRV include all classes of genes: unbiased in expression between the sexes, female-biased, and male-biased. Many of the genes affected by YRV are related to adaptive traits (e. g., thermal tolerance) or sexual selection (e. g., pheromone reception). The discovery of YRV is potentially of great significance because it suggests that the Y chromosome in all organisms, including humans, is very special in mediating major genomic effects on gene expression through its large complement of noncoding DNA. The proposed experiments will test the hypothesis that YRV results from variation in the copy number of Y-linked sequences that compete with the autosomal and X-linked genes for binding with limiting amounts of chromatin-associated proteins that affect levels of gene expression. The proposed experiments will also test the hypothesis that YRV is mediated by regulatory pathways associated with position-effect variegation (PEV) and/or repeat- associated small interfering RNA (rasiRNA). The proposed research is therefore transformative because it may radically change our understanding of the role of Y chromosome noncoding sequences in accounting for phenotypic variation through its effects on gene regulation. Selection acting through regulatory effects may drive the rapid evolution of noncoding sequences in the Y chromosome, which are evolutionarily much more dynamic than single-copy sequences. This view challenges the current paradigm that such sequences are mere "junk" DNA evolving neutrally. The proposed experiments will also identify a set of YRV-affected candidate genes associated with thermal tolerance of spermatogenesis, a key biological factor in limiting the ecological range of many insects including the mosquitoes that transmit malaria. We will also develop theoretical models for the population dynamics of polymorphic Y chromosomes associated with YRV to determine whether a model based on competitive binding is possible with realistic values of the parameters. The relevance to the NIH mission is that our findings about the Drosophila Y chromosome are likely to be quite general among organisms with genomes rich in heterochromatin including the human genome. Hence we predict that important phenotypic variation affecting human health and disease will ultimately be traced to variation in heterochromatin in human chromosomes. The long-range goal of this research is to understand the regulatory role of the Y chromosome in genetic variation and evolution. Eventually the pericentromeric heterochromatin of the X chromosome and autosomes must also be studied, but the Drosophila Y chromosome is the place to start because of its low content of coding sequences, its high content of noncoding repetitive sequences, its relative ease of genetic manipulation, and the genetic resources available. Relevance The relevance of this research is that it investigates the molecular mechanisms and adaptive significance of newly discovered effects of the Y chromosome on gene expression, which may have widespread implications for the role of the Y chromosome in humans and other organisms. Public Health Relevance: The Y chromosome is widely considered as a gene-poor, slowly degenerating wasteland of genomic DNA whose only functions are to serve as a pairing partner for the X and to carry genes for maleness or male fertility in different species. Our preliminary findings strongly suggest that this view is false. Our novel finding is that Y chromosome polymorphisms differentially affect the level of expression of many hundreds of genes across the genome. We believe that these effects are mediated by rapidly evolving, little understood regions of the Y chromosome containing sequence repeats of noncoding DNA. The experiments proposed are transformative in challenging the current view of Y-chromosome affects on the expression of other genes, and of how the Y chromosome changes through time. We predict that important phenotypic variation affecting human health and disease will ultimately be traced to variation in sequence repeats of noncoding DNA in the human Y chromosome.

Public Health Relevance

The Y chromosome is widely considered as a gene-poor, slowly degenerating wasteland of genomic DNA whose only functions are to serve as a pairing partner for the X and to carry genes for maleness or male fertility in different species. Our preliminary findings strongly suggest that this view is false. Our novel finding is that Y chromosome polymorphisms differentially affect the level of expression of many hundreds of genes across the genome. We believe that these effects are mediated by rapidly evolving, little understood regions of the Y chromosome containing sequence repeats of noncoding DNA. The experiments proposed are transformative in challenging the current view of Y-chromosome affects on the expression of other genes, and of how the Y chromosome changes through time. We predict that important phenotypic variation affecting human health and disease will ultimately be traced to variation in sequence repeats of noncoding DNA in the human Y chromosome.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084236-04
Application #
8213572
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Eckstrand, Irene A
Project Start
2009-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$296,382
Indirect Cost
$119,964
Name
Harvard University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Sackton, Timothy B; Corbett-Detig, Russell B; Nagaraju, Javaregowda et al. (2014) Positive selection drives faster-Z evolution in silkmoths. Evolution 68:2331-42
Corbett-Detig, Russell B; Zhou, Jun; Clark, Andrew G et al. (2013) Genetic incompatibilities are widespread within species. Nature 504:135-7
Sackton, Timothy B; Hartl, Daniel L (2013) Meta-analysis reveals that genes regulated by the Y chromosome in Drosophila melanogaster are preferentially localized to repressive chromatin. Genome Biol Evol 5:255-66
Rogers, Rebekah L; Hartl, Daniel L (2012) Chimeric genes as a source of rapid evolution in Drosophila melanogaster. Mol Biol Evol 29:517-29
Paredes, Silvana; Branco, Alan T; Hartl, Daniel L et al. (2011) Ribosomal DNA deletions modulate genome-wide gene expression: "rDNA-sensitive" genes and natural variation. PLoS Genet 7:e1001376
Zhou, Jun; Lemos, Bernardo; Dopman, Erik B et al. (2011) Copy-number variation: the balance between gene dosage and expression in Drosophila melanogaster. Genome Biol Evol 3:1014-24
Costanzo, Marna S; Hartl, Daniel L (2011) The evolutionary landscape of antifolate resistance in Plasmodium falciparum. J Genet 90:187-90
Sackton, Timothy B; Montenegro, Horacio; Hartl, Daniel L et al. (2011) Interspecific Y chromosome introgressions disrupt testis-specific gene expression and male reproductive phenotypes in Drosophila. Proc Natl Acad Sci U S A 108:17046-51
Rogers, Rebekah L; Bedford, Trevor; Lyons, Ana M et al. (2010) Adaptive impact of the chimeric gene Quetzalcoatl in Drosophila melanogaster. Proc Natl Acad Sci U S A 107:10943-8
Lemos, Bernardo; Branco, Alan T; Hartl, Daniel L (2010) Epigenetic effects of polymorphic Y chromosomes modulate chromatin components, immune response, and sexual conflict. Proc Natl Acad Sci U S A 107:15826-31

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