Tariq et al (2011) heterotaxy-spectrum cardiovascular disorders are challenging for traditional genetic analyses because of clinical and genetic heterogeneity, variable expressivity, and non-penetrance. In this study, high-resolution single nucleotide polymorphisms (SNPs) genotyping and exon-targeted array comparative genomic hybridization (CGH) platforms were coupled to whole-exome sequencing to identify a novel disease candidate gene. SNP genotyping identified absence-of-heterozygosity regions in the heterotaxy proband on chromosomes 1, 4, 7, 13, 15, 18, consistent with parental consanguinity. Subsequently, whole-exome sequencing of the proband identified 26,065 coding variants, including 18 non-synonymous homozygous changes not present in dbSNP132 or 1000 Genomes. Of these 18, only 4 -- 1 each in CXCL2, SHROOM3, CTSO, RXFP1 -- were mapped to the absence-of-heterozygosity regions, each of which was flanked by more than 50 homozygous SNPs, confirming recessive segregation of mutant alleles. Sanger sequencing confirmed the SHROOM3 homozygous missense mutation and it was predicted as pathogenic by 4 bio-informatic tools. SHROOM3 has been identified as a central regulator of morphogenetic cell shape changes necessary for organogenesis and can physically bind ROCK2, a rho kinase protein required for left-right patterning. Screening 96 sporadic heterotaxy patients identified 4 additional patients with rare variants in SHROOM3. The authors concluded that using whole exome sequencing, the authors identify a recessive missense mutation in SHROOM3 associated with heterotaxy syndrome and identify rare variants in subsequent screening of a heterotaxy cohort, suggesting SHROOM3 as a novel target for the control of left-right patterning. This study revealed the value of SNP genotyping coupled with high-throughput sequencing for identification of high yield candidates for rare disorders with genetic and phenotypic heterogeneity.
Molecular genetic tools and genomic resources have been developed for cowpea with an objective of enhancing breeding programs for the improvement of cowpea varieties for the United States, India, Brazil, and numerous countries in Africa and Asia. These genomic resources have been integrated by using a 1536-single nucleotide polymorphism (SNP) genotyping platform and include an expressed sequence tag (EST)-derived SNP cowpea consensus genetic map, known syntenic relationships between cowpea, M. truncatula, G. max and A. thaliana, and a cowpea EST sequence collection housed in HarvEST:Cowpea database () (Muchero et al. ; Lucas et al. ). The cowpea physical map which has been anchored to the cowpea consensus genetic map using the same SNP genotyping platform is currently available (). In addition, more than 500 diverse cowpea accessions have been SNP-genotyped and a first draft of the cowpea genome sequence has been assembled (). These resources will enable dissection of underlying genetic components of target agronomic traits using quantitative trait locus (QTL) analysis and association mapping. In this study, greenhouse inoculation experiments were used to identify QTLs conferring resistance against Fot race 4 in three cowpea recombinant inbred line (RIL) populations. Two loci which confer resistance to Fot race 4 were identified, Fot4-1 and Fot4-2. The target outcome of this study will be to develop molecular markers closely linked to the Fot4-1 and Fot4-2 resistance genes for application in resistance breeding.
Genetic Resources, Genome Mapping and Evolutionary …
Books: Our knowledge of population geneticsincreases day by day. A page such as this one can serve as little more than avery brief, simplified introduction, with an eye toward the subject's Siciliancontext (our remote African, then Asian and finally European forebears). For moredetailed explanations of human genetic history (and "pre-history") wesuggest the following books. Each differs in its approach, but despite occasionalredundancy these works complement each other surprisingly well. For example, thebook by Luigi Luca Cavalli-Sforza, the dean of population genetic studies, has aninteresting cultural and linguistic perspective. If we could make a singlesuggestion to somebody seriously interested in this topic, it would be to readall of these books, plus the one (following the list) on theIndo-Europeans.