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Four loci explain 83% of size variation in the horse 总被引:1,自引:0,他引:1
S Makvandi-Nejad GE Hoffman JJ Allen E Chu E Gu AM Chandler AI Loredo RR Bellone JG Mezey SA Brooks NB Sutter 《PloS one》2012,7(7):e39929
Horse body size varies greatly due to intense selection within each breed. American Miniatures are less than one meter tall at the withers while Shires and Percherons can exceed two meters. The genetic basis for this variation is not known. We hypothesize that the breed population structure of the horse should simplify efforts to identify genes controlling size. In support of this, here we show with genome-wide association scans (GWAS) that genetic variation at just four loci can explain the great majority of horse size variation. Unlike humans, which are naturally reproducing and possess many genetic variants with weak effects on size, we show that horses, like other domestic mammals, carry just a small number of size loci with alleles of large effect. Furthermore, three of our horse size loci contain the LCORL, HMGA2 and ZFAT genes that have previously been found to control human height. The LCORL/NCAPG locus is also implicated in cattle growth and HMGA2 is associated with dog size. Extreme size diversification is a hallmark of domestication. Our results in the horse, complemented by the prior work in cattle and dog, serve to pinpoint those very few genes that have played major roles in the rapid evolution of size during domestication. 相似文献
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Mdm2, a regulator of the tumor suppressor p53, is frequently overexpressed in human malignancies. Mdm2 also has unresolved, p53-independent functions that contribute to tumorigenesis. Here, we show that increased Mdm2 expression induced chromosome/chromatid breaks and delayed DNA double-strand break repair in cells lacking p53 but not in cells with a mutant form of Nbs1, a component of the Mre11/Rad50/Nbs1 DNA repair complex. A 31-amino-acid region of Mdm2 was necessary for binding to Nbs1. Mutation of conserved amino acids in the Nbs1 binding domain of Mdm2 inhibited Mdm2-Nbs1 association and prevented Mdm2 from delaying phosphorylation of H2AX and ATM-S/TQ sites, repair of DNA breaks, and resolution of DNA damage foci. Similarly, the mutation of eight amino acids in the Mdm2 binding domain of Nbs1 inhibited Mdm2-Nbs1 interaction and blocked the ability of Mdm2 to delay DNA break repair. Both Nbs1 and ATM, but not the ubiquitin ligase activity of Mdm2, were necessary to inhibit DNA break repair. Only Mdm2 with an intact Nbs1 binding domain was able to increase the frequency of chromosome/chromatid breaks and the transformation efficiency of cells lacking p53. Therefore, the interaction of Mdm2 with Nbs1 inhibited DNA break repair, leading to chromosome instability and subsequent transformation that was independent of p53. 相似文献
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The evolution of gene families can be best understood by studying the modern organization and functions of family members, and by comparing parallel families in different species. In this study, the CYP2ABFGST gene cluster has been characterized in rat and compared to the syntenic clusters in mouse and human, providing an interesting example of gene family evolution. In the rat, 18 loci from six subfamilies have been identified by specifically amplifying and sequencing gene fragments from cloned DNA, and have been exactly placed on chromosome 1. The overall organization of the gene cluster in rat is relatively simple, with genes from each subfamily in tandem, and is more similar to the mouse than to the human cluster. We have reconstructed the probable structure of the CYP2ABFGST cluster in the common ancestor of primates and rodents, and inferred a model of the evolution of this gene cluster in the three species. Numerous nontandem and block duplications, inversions, and translocations have occurred entirely inside the cluster, indicating that pairing between duplicate genes is keeping the rearrangements within the cluster region. The initial tandem duplication of a CYP2 gene in an early mammalian ancestor has made this region particularly subject to such localized rearrangements. Even if duplicated genes do not have a large-scale effect on chromosomal rearrangements, on a local level clustered gene families may have contributed significantly to the genomic complexity of modern mammals. 相似文献
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Recombinant monoclonal antibodies (mAbs) have become an important category of biological therapeutics. mAbs share the same structures and biological functions as endogenous IgG molecules. One function is complement-dependent cytotoxicity (CDC) initiation by binding of C1q. Traditionally, ELISA methods have been utilized to measure C1q binding. A new robust capture method was established in this study to measure the binding affinity of C1q to antibodies by surface plasmon resonance (SPR). The utility of this method was demonstrated by determination of the difference in IgG subclass specificity of C1q binding. 相似文献
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Mireia Medrano David Aguinaga Irene Reyes-Resina Enric I. Canela Josefa Mallol Gemma Navarro Rafael Franco 《Molecular neurobiology》2018,55(6):4718-4730
The hypothalamus is a key integrator of nutrient-seeking signals in the form of hormones and metabolites originated in both the central nervous system and the periphery. The main autocrine and paracrine target of orexinergic-related hormones such as leptin, orexin/hypocretin, and ghrelin are neuropeptide Y neurons located in the arcuate nucleus of the hypothalamus. The aim of this study was to investigate the expression and the molecular and functional relationships between leptin, orexin/hypocretin and ghrelin receptors. Biophysical studies in a heterologous system showed physical interactions between them, with potential formation of heterotrimeric complexes. Functional assays showed robust allosteric interactions particularly different when the three receptors are expressed together. Further biochemical and pharmacological assays provided evidence of heterotrimer functional expression in primary cultures of hypothalamic neurons. These findings constitute evidence of close relationships in the action of the three hormones already starting at the receptor level in hypothalamic cells. 相似文献