Heritability of alternative splicing in the human genome.
Alternative pre-mRNA splicing increases proteomic diversity and provides a potential mechanism underlying both phenotypic diversity and susceptibility to genetic disorders in human populations. To investigate the variation in splicing among humans on a genome-wide scale, we use a comprehensive exon-targeted microarray to examine alternative splicing in lymphoblastoid cell lines (LCLs) derived from the CEPH HapMap population. We show the identification of transcripts containing sequence verified exon skipping, intron retention, and cryptic splice site usage that are specific between individuals. A number of novel alternative splicing events with no previous annotations in either the RefSeq and EST databases were identified, indicating that we are able to discover de novo splicing events. Using family-based linkage analysis, we demonstrate Mendelian inheritance and segregation of specific splice isoforms with regulatory haplotypes for three genes: OAS1, CAST, and CRTAP. Allelic association was further used to identify individual SNPs or regulatory haplotype blocks linked to the alternative splicing event, taking advantage of the high-resolution genotype information from the CEPH HapMap population. In one candidate, we identified a regulatory polymorphism that disrupts a 5' splice site of an exon in the CAST gene, resulting in its exclusion in the mutant allele. This report illustrates that our approach can detect both annotated and novel alternatively spliced variants, and that such variation among individuals is heritable and genetically controlled.
Department of Human Genetics, McGill University, Montréal, Québec, Canada.
Tony
T
Kwan
David
D
Benovoy
Christel
C
Dias
Scott
S
Gurd
David
D
Serre
Harry
H
Zuzan
Tyson A
TA
Clark
Anthony
A
Schweitzer
Michelle K
MK
Staples
Hui
H
Wang
John E
JE
Blume
Thomas J
TJ
Hudson
Rob
R
Sladek
Jacek
J
Majewski
D017398:Alternative Splicing; D001483:Base Sequence; D002460:Cell Line; D005091:Exons; D015894:Genome, Human; D006801:Humans; D040582:Inheritance Patterns; D008954:Models, Biological; D008957:Models, Genetic; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA