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Genetics of Height Variation« Back to Volume 23, Issue 1, March 2007 - Table of Contents A large number of human genetic disorders including chromosomal and single gene disorders have short stature as a significant component. Aside from these conditions, genetic factors have long been known to influence height within the normal range (ie, short parents have short children). Linkage studies have pointed to a number of chromosomal regions that contain one or more gene(s) that affect height, but the identities of specific genes and how they influence height have eluded investigators. Liu and colleagues offer evidence that height is affected by the interactions of genes located in 2 different chromosomal regions, a phenomenon referred to as epistasis. Height information was collected on 3726 Caucasians from 434 pedigrees as part of ongoing studies in the Osteoporosis Research Center of Creighton University to identify genes that contribute to common human traits. Although most of the kindreds contained less than 10 individuals, many were larger, and 14 families had over 40 members who were studied. The many large families provided a large number of relative pairs for height comparisons, which increased the statistical power of the linkage analysis. Genotyping was performed with microsatellite markers spaced on average about 9 cM apart. The initial analysis was designed to identify individual chromosomal regions linked to height variability. More specifically multipoint and two-point LOD scores were calculated using Sequential Oligogenic Linkage Analysis Routines (SOLAR). The results reported in early 2006 (Liu et al, Hum Genet 2006) suggested linkage for chromosome regions 9q22 and Xq24 and possible linkage at 6p21 and 2q21. In the second publication reviewed here (Liu et al, J Clin Invest 2006), the investigators further analyzed their data for 3 loci (9q22, 6p21, 2q21) using statistical tests for pairwise epistatic interactions between the 3 loci under different hypothetical models. This approach allowed them to compare the effect of the individual loci with the additive effects of paired loci and with the interactive or epistatic effects of the paired loci. The epistatic model implies a genetic influence that is greater than simply adding the influences of the paired loci together. The results revealed the most likely model to explain the results is a 2 locus epistatic model involving chromosome regions 6p21 and 2q21. In other words, the analysis suggests that a functional interaction between genes residing in these 2 regions somehow influences height. After making statistical corrections, the authors suggested that the fraction of height variation due to the interaction between these 2 regions is approximately 20%. The authors discussed the specific gene loci that map to the 6p21 and 2q21 chromosome regions. For example, 6p21 contains genes for the α–2 chain of type XI collagen, the transcription factor, RUNX2 and the retinoid X receptor-ß, RXRB, all of which have known functions in linear skeletal growth. No obvious growth-related genes have been mapped to region 2q21. Editor’s CommentThis report is very interesting, but not very surprising. It is becoming clear from investigations of the skeletal growth plate that its biology and function are regulated by mechanisms that typically involve molecular interactions of multiple gene products (proteins) often in the form of linear pathways, such as signal transduction pathways or in multicomponent complexes, such as signaling platforms and transcriptional complexes that act like complicated machines. Such pathways and complexes provide means for products of different genes to interact functionally, which is presumably what happens in this case, with proteins whose genes map to chromosomes 2 and 6. William A. Horton, MD
« Back to Volume 23, Issue 1, March 2007 - Table of Contents
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Volume 24 Number 1
May 2008
www.GGHjournal.com
ISSN 1932-9032
