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Genomics in the Journals: May 30, 2013

NEW YORK (GenomeWeb News) – A Current Biology study by a Chinese and South Korean team suggests the unusual coat color of white Bengal tigers — which have dark stripes set against a background of white fur — can be traced back to a gene already implicated in pigmentation in other vertebrate animals, including humans, horses, mice, chicken, and medaka fish.

In their effort to narrow in on loci linked to the autosomal recessive white coat trait, the researchers used restriction-site-associated DNA sequencing, or RAD-seq, and whole-genome sequencing to do a genome-wide mapping analysis on seven white and nine wild-type, or orange, tigers from a related pedigree.

Using whole-genome sequence data from one male and two female tiger parents and RAD-seq profiles for their 13 offspring, investigators were able to home in on cat chromosome A1 locus, which had apparent ties to white coat coloring in the tigers.

Targeted testing of the multi-gene-containing locus in 130 more unrelated tigers suggested that the cause of the white coat is a mutation in a pigmentation-related transporter gene called SLC45A2 that leads to an amino acid swap in the resulting protein.

Stanford University School of Medicine's Aaron Gitler and colleagues from the US and Australia used exome sequencing to uncover potential genetic culprits in sporadic cases of amyotrophic lateral sclerosis, or ALS — work that they described in Nature Neuroscience.

In an effort to better understand non-inherited forms of the deadly, progressive neurodegenerative condition, commonly known as Lou Gehrig's disease, the team sequenced the exomes of 47 individuals with sporadic ALS and their unaffected parents.

When they sorted through this sequence data, the researchers found an increase in de novo mutations in the exomes of those with ALS, particularly within genes contributing to chromatin regulation and remodeling.

For instance, five of the 25 de novo alterations appeared in chromatin-related genes. Among the affected genes was SS18L1, a member of the neuronal chromatin remodeling complex that appeared to influence neural function in the team's subsequent mouse model experiments.

"Now we have a list of candidate genes we can pursue," first author Alessandra Chesi, a post-doctoral researcher in Gitler's Stanford lab, said in a statement.

"We haven't proven that these mutations cause ALS," she noted, "but we've shown, at least in the context of SS18L1, that the mutation carried by some patients is damaging to the protein and affects the ability of mouse motor neurons to form dendrites."

A pair of Nature Genetics papers by independent research teams pointed to new genetic contributors to congenital heart disease.

The first, by an international group led by investigators in the UK, implicated a chromosome 4 region in risk of a type of congenital heart disease malformation called ostium secundum atrial septal defect.

For that study, researchers did a genome-wide association study involving 1,995 individuals of European ancestry, each with one of three forms of congenital heart disease. When they compared genotyping profiles of individuals from the affected group with those of the 5,159 unaffected controls, authors of that study saw a site near the chromosome 4 genes MSX1 and STX18 that coincided with the presence of atrial septal defect — an association that they verified through follow-up testing on another 417 individuals with the malformation and 2,520 without.

In another Nature Genetics paper, Chinese researchers described the GWAS that they used to find two loci linked to congenital heart malformation in the Han Chinese population. The initial phase of that association study, which included 945 cases and 1,246 controls, yielded eight suspicious SNPs.

Investigators involved with that study solidified ties between congenital heart malformation and variants at two sites — a chromosome 1 site neighboring a gene called TBX15 and a chromosome 4 locus in the MAML3 gene — through a two-stage validation process involving another 2,160 individuals with congenital heart malformation and 3,866 without.

An international team bent on understanding the heritability of socially, economically, and psychologically relevant traits has tracked down a trio of SNPs associated with individuals' level of educational attainment.

As they reported in the early, online edition of Science, members of the Social Science Genetic Association Consortium started by bringing together data for 101,069 individuals genotyped through numerous past studies. All of these participants were included in an analysis looking for variants linked to the number of years individuals attended school, while a subset of 95,472 participants were tested for genetic associations with the completion of college-level education.

During this discovery stage, the research team unearthed one SNP with genome-wide significant ties to individuals' number of educational years. Two more variants were significantly linked to college completion and several other variants had suggestive associations with one or both traits.

All three genome-wide significant SNPs were verified in a validation cohort of 25,490 individuals, study authors noted, though the overall boost in educational attainment linked to each allele was low.

"We have now taken a small but important first step toward identifying the specific genetic variants that predict educational attainment," co-author Dalton Conley, a sociology researcher at New York University and SSGAC advisory board member, said in a statement.

"Armed with this knowledge," he continued, "we can now begin to examine how other factors — including public policy, parental roles, and economic status — dampen or amplify genetic effects and ultimately devise better remedies to bolster educational outcomes."

Genomics In The Journals is a weekly feature pointing readers to select, recently published articles involving genomics and related research.