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McIntyre, Lauren M.; Bono, Lisa M.; Génissel, Anne; Westerman, Richard P.; Junk, Damion; Telonis‐Scott, Marina; Harshman, Larry; Wayne, Marta L.; Kopp, Artyom; Nuzhdin, Sergey V.

doi:10.1186/gb-2006-7-8-r79

Cited by 94 publications

(58 citation statements)

References 94 publications

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“…Among genes that are highly expressed in males compared to females in all three species, we found a significant over-representation of genes involved in RNA splicing, RNA binding, and RNA processing (P < 0.01) (see Supplemental Table S9). This latter observation is consistent with the notion that sexually dimorphic alternative splicing is an important biological mechanism (Stolc et al 2004;McIntyre et al 2006). …”

Section: Resultssupporting

confidence: 80%

“…These results, together with the observation of an enrichment of genes involved in RNA splicing among sexually dimorphic genes, may point to functionally conserved sexually dimorphic alternative splicing in primates. Indeed, such a mechanism has been previously reported in flies (McIntyre et al 2006). That said, due to the large FDR in our analysis and the potential for unobserved confounding factors that might affect FDR calculations (Leek and Storey 2007), these results should be treated with caution.…”

Section: Analysis Of Exon Usage and Alternative Splicingmentioning

confidence: 72%

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Sex-specific and lineage-specific alternative splicing in primates

Blekhman¹,

Marioni²,

et al. 2009

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Comparative studies of gene regulation suggest an important role for natural selection in shaping gene expression patterns within and between species. Most of these studies, however, estimated gene expression levels using microarray probes designed to hybridize to only a small proportion of each gene. Here, we used recently developed RNA sequencing protocols, which sidestep this limitation, to assess intra-and interspecies variation in gene regulatory processes in considerably more detail than was previously possible. Specifically, we used RNA-seq to study transcript levels in humans, chimpanzees, and rhesus macaques, using liver RNA samples from three males and three females from each species. Our approach allowed us to identify a large number of genes whose expression levels likely evolve under natural selection in primates. These include a subset of genes with conserved sexually dimorphic expression patterns across the three species, which we found to be enriched for genes involved in lipid metabolism. Our data also suggest that while alternative splicing is tightly regulated within and between species, sex-specific and lineage-specific changes in the expression of different splice forms are also frequent. Intriguingly, among genes in which a change in exon usage occurred exclusively in the human lineage, we found an enrichment of genes involved in anatomical structure and morphogenesis, raising the possibility that differences in the regulation of alternative splicing have been an important force in human evolution.[Supplemental material is available online at http://www.genome.org. The RNA-seq data have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under series accession no. GSE17274.]Changes in gene regulation are thought to play an important role in adaptive evolution and speciation (Britten and Davidson 1971;King and Wilson 1975;Jin et al. 2001;Carroll 2003Carroll , 2008Abzhanov et al. 2004;Iftikhar et al. 2004;Shapiro et al. 2004;Taron et al. 2004;Wray 2007). In support of this notion, comparative genome-wide studies of gene regulation within and between populations and species have revealed evidence consistent with the action of both stabilizing as well as directional selection on gene expression levels (Oleksiak et al. 2002;Lemos et al. 2005;Rifkin et al. 2005;Gilad et al. 2006;Whitehead and Crawford 2006). Most of these studies, however, focused on estimates of overall gene expression levels, probably because prior to the development of next-generation sequencing, it was very challenging to characterize expression level variation of individual exons on a genome-wide scale.Indeed, previous studies of alternative splicing patterns in mammalian species focused on relatively small numbers of exons and genes. For example, Su et al. (2008) studied variation in exon usage and alternative splicing in liver samples from a number of mouse strains from both sexes, by using a custom microarray designed to probe the expression levels of 25,760 exons and exonexon junctions f...

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Section: Resultssupporting

confidence: 80%

Section: Analysis Of Exon Usage and Alternative Splicingmentioning

confidence: 72%

Sex-specific and lineage-specific alternative splicing in primates

Blekhman¹,

Marioni²,

et al. 2009

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“…This observation suggests the existence of dedicated regulatory programs that coordinately control multiple AS events. Such programs are evident, for example, in Drosophila sex determination (19) and mammalian synaptic transmission (20,21) and strongly argue for the biological relevance of AS.…”

Section: Biological Relevancementioning

confidence: 99%

Genome-wide Analysis of Alternative Pre-mRNA Splicing

Ben‐Dov

Hartmann

Lundgren

et al. 2008

Journal of Biological Chemistry

125

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Alternative splicing of mRNA precursors allows the synthesis of multiple mRNAs from a single primary transcript, significantly expanding the information content and regulatory possibilities of higher eukaryotic genomes. High-throughput enabling technologies, particularly large-scale sequencing and splicing-sensitive microarrays, are providing unprecedented opportunities to address key questions in this field. The picture emerging from these pioneering studies is that alternative splicing affects most human genes and a significant fraction of the genes in other multicellular organisms, with the potential to greatly influence the evolution of complex genomes. A combinatorial code of regulatory signals and factors can deploy physiologically coherent programs of alternative splicing that are distinct from those regulated at other steps of gene expression. Pre-mRNA splicing and its regulation play important roles in human pathologies, and genome-wide analyses in this area are paving the way for improved diagnostic tools and for the identification of novel and more specific pharmaceutical targets.Removal of introns from pre-mRNAs is an essential step in eukaryotic gene expression (see Fig. 1A). Alternative patterns of intron removal allow the synthesis of multiple mRNAs from a single gene encoding different proteins (see Fig. 1B). This minireview focuses on how the recent application of high-throughput technologies is providing a novel and empowered perspective to address the following four outstanding questions in the field of alternative pre-mRNA splicing (AS). 3 PrevalenceAlthough early estimates suggested that AS affects only a small fraction of human genes, large-scale genome and transcriptome sequencing projects allowing extensive alignments of mRNA with genomic sequences (see Fig. 2A) indicate that the majority of human genes are alternatively spliced (1). Splicing-sensitive microarrays (see Fig. 2B) provide independent confirmation of this high incidence. Using a variety of experimental designs and biological samples, several of these studies have produced consistent estimates of 70 -80% of alternatively spliced genes in the human genome (2-4). The production of alternatively spliced transcripts is therefore a general feature of human genes to be incorporated in biological and medical studies, from the design of gene knock-out/down experiments to molecular diagnostics or drug screens.In addition, in-depth analysis of individual genes frequently reveals novel AS isoforms, suggesting that transcript diversity is far from fully annotated in current data bases. Furthermore, recent analyses of HapMap cell lines document variations in AS among different individuals, an observation with significant basic and medical implications (5,6).Is the prevalence of AS uniform across organisms, or does it increase with the evolution of complexity? In silico comparative analyses have provided contradictory answers to this question. Although some data support an increased incidence of AS in vertebrates (7), it is also clear that ...

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“…In adult flies, approximately half of all genes are differentially expressed in males and females (2). As many as 25% of genes may experience sex-specific splicing (3). Gene expression may mediate sexual dimorphism either by limiting expression to one sex only (sex-limited expression), or by changing expression for the same genes between sexes (differential expression).…”

mentioning

confidence: 99%

Simpler mode of inheritance of transcriptional variation in maleDrosophila melanogaster

Wayne

Telonis‐Scott

Bono

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Sexual selection drives faster evolution in males. The X chromosome is potentially an important target for sexual selection, because hemizygosity in males permits accumulation of alleles, causing tradeoffs in fitness between sexes. Hemizygosity of the X could cause fundamentally different modes of inheritance between the sexes, with more additive variation in males and more nonadditive variation in females. Indeed, we find that genetic variation for the transcriptome is primarily additive in males but nonadditive in females. As expected, these differences are more pronounced on the X chromosome than the autosomes, but autosomal loci are also affected, possibly because of X-linked transcription factors. These differences may be of evolutionary significance because additive variation responds quickly to selection, whereas nonadditive genetic variation does not. Thus, hemizygosity of the X may underlie much of the faster male evolution of the transcriptome and potentially other phenotypes. Consistent with this prediction, genes that are additive in males and nonadditive in females are overrepresented among genes responding to selection for increased mating speed.microarray ͉ sexual antagonism ͉ sexual conflict ͉ sexual selection ͉ transcription

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Cited by 94 publications

References 94 publications

Sex-specific and lineage-specific alternative splicing in primates

Sex-specific and lineage-specific alternative splicing in primates

Genome-wide Analysis of Alternative Pre-mRNA Splicing

Simpler mode of inheritance of transcriptional variation in maleDrosophila melanogaster

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