The American Journal of Human Genetics – Cell

Volume93,Issue 6:December5,2013

On the cover: John Borden Graham, M.D., President, American Society of Human Genetics, 1972. John Graham is remembered as a pioneer in the genetics of blood coagulation and genetics education. He was born in 1918 in Goldsboro and earned a bachelors degree from Davidson College in 1938. He began his medical training by studying the basic sciences at University of North Carolina at Chapel Hill (UNC-CH) and completed his M.D. at Cornell University in 1942. After a short pathology residency, he entered the US Army, where he served as a surgeon in the Pacific Theater. He returned to Chapel Hill in 1946 to join the Department of Pathology as an instructor. He remained at UNC-CH until his formal retirement in 1985. Graham continued to participate in departmental activities and attended departmental grand rounds until the day before his death in 2004. In 1954, Graham established the first formal course in medical genetics at UNC-CH. Grahams research focused on hematology and blood clotting initially through collaboration with Kenneth Brinkhous, who was characterizing canine hemophilia. Together, they demonstrated X-linkage and viability of homozygous females (Brinkhous and Graham [1950]. Science 111, 723724). He is credited with the characterization of clotting factor X and X-linked vitamin-D-resistant rickets. He remembered when the Society numbered 200 members in 1954 and that meetings were held during summer vacations on university campuses with families in tow. He contrasted those days with the very large Society meetings held at posh urban hotels in the mid-1980s (Graham [1985], Norma Berryhill Distinguished Lecture, https://secure.dev.unc.edu/MedFound/graham13-27.pdf). Although no recording of his presidential address from the 1972 annual meeting held in Philadelphia can be found, some of Grahams articles represent recorded presentations. Examples include his 1956 review of hemophilia drawn from a session at the 1955 ASHG annual meeting (Am. J. Hum. Genet. 8, 6379) and a 1959 discussion on vascular hemophilia, which includes references to Homers Odyssey (J. Med. Educ. 34, 385396). These allow the reader to enjoy Grahams garrulous and erudite style. This image of Graham was drawn by Peter James Field from a photograph provided by the University of North Carolina Department of Pathology and is used with permission.

Click here for a high-resolution version of the cover.

Each week, The American Journal of Human Genetics publishes papers online ahead of the print issue. Here are the latest:

All in the Family In the age of next-generation sequencing, linkage analysis might seem old fashioned, and perhaps even ill suited for the pursuit of variants that contribute to complex phenotypes. Indeed, many have turned to genome-wide association studies and exome-wide sequencing studies for such investigations. In this issue, Rosenthal et al. show that family studies can be adapted, and indeed strengthened, by the integration with 21st century technology and resources. Through a combination of linkage analysis and exome sequencing, the authors identified a SLC25A40 missense change that might contribute to high triglyceride levels. They then harnessed the power of the NHLBI Exome Sequencing Project to identify an association between SLC25A40 variants and high triglyceride levels.

Regulating lincRNA Expression Unlike that of protein-coding genes, the function of the majority of large intergenic noncoding RNAs (lincRNAs) remains unknown. To gain further insight into the potential roles of lincRNAs, Popadin et al. used a genome-wide approach to characterize the cis expression quantitative trait loci (cis-eQTLs) and DNA-methylation patterns that contribute to lincRNA expression variability across fibroblasts, lymphoblastoid cell lines, and T cells derived from 195 European individuals. In general, lincRNA cis-eQTLs affected neighboring downstream protein-coding genes, suggesting that lincRNAs might also act as enhancers. Because lincRNAs are relatively young, it remains to be seen whether the variants that contribute to variable expression are under selection.

Functional Characterization of Breast-Cancer-Associated SNPs Variants near FGFR2 have been implicated in estrogen receptor (ER)-positive breast cancer, but it remains unclear how this locus contributes to disease progression. In this study, Meyer et al. used the iCOGS chip to fine map this region. They identified three independent risk signals and further prioritized the variants by using a variety of assays. ChIP assays demonstrated allele-specific binding of FOXA1 and E2F1. Because FOXA1 and ER are involved in conferring estrogen responsiveness, these results support the involvement of this locus in ER-positive breast cancer.

Ciliary Involvement in Morbid Obesity Substantial effort has been spent on identifying genes that are associated with obesity and metabolic dysfunction. In this issue, Shalata and colleagues identified a homozygous nonsense mutation in CEP19 in a large, consanguineous family where affected individuals are morbidly obese and have an average body mass index of 48.7. Moreover, Cep19-knockout mice were nearly twice as heavy as their wild-type littermates, as well as hyperphagic, glucose intolerant, and insulin resistant in comparison to the wild-type mice. CEP19 localized to the centriole and basal body of primary cilia, suggesting the need for further explorations into the role of cilia in regulating metabolism.

Exploring T2D Exomes In recent years, the hunt for variants associated with common diseases has focused on uncovering common variants. More recently, however, spurred by the decreased cost of sequencing, investigators have begun to search for rare variants of large effect. In this issue, Lohmueller et al. explore the possibility that the underlying genetic architecture of type 2 diabetes (T2D) is driven by rare variants clustered in a small number of genes. Single-marker and gene-based association tests failed to reveal significant associations, suggesting that if rare variants do contribute to T2D risk, they will not be limited to a small number of genes.

A Polymorphism in IRF4 Affects Human Pigmentation through a Tyrosinase-Dependent MITF/TFAP2A Pathway In this study, Praetorius et al. demonstrate that a SNP associated with sun-exposure sensitivity lies within a melanocyte-specific enhancer of IRF4 transcription, thus identifying a noncoding polymorphism that affects a phenotype through modulation of a developmental gene regulatory network.

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The American Journal of Human Genetics - Cell