Modulation of ligand selectivity associated with activation of the transmembrane region of the human follitropin receptor.

Recently, three naturally occurring mutations in the serpentine region of the FSH receptor (FSHr) (D567N and T449I/A) have been identified in three families with spontaneous ovarian hyperstimulation syndrome (OHSS). All mutant receptors displayed abnormally high sensitivity to human chorionic gonadotropin and, in addition, D567N and T449A displayed concomitant increase in sensitivity to TSH and detectable constitutive activity. In the present study, we have used a combination of site-directed mutagenesis experiments and molecular modeling to explore the mechanisms responsible for the phenotype of the three OHSS FSHr mutants. Our results suggest that all mutations lead to weakening of interhelical locks between transmembrane helix (TM)-VI and TM-III, or TM-VI and TM-VII, which contributes to maintaining the receptor in the inactive state. They also indicate that broadening of the functional specificity of the mutant FSHr constructs is correlated to their increase in constitutive activity. This relation between basal activity and functional specificity is a characteristic of the FSHr, which is not shared by the other glycoprotein hormone receptors. It leads to the interesting suggestion that different pathways have been followed during primate evolution to avoid promiscuous stimulation of the TSHr and FSHr by human chorionic gonadotropin. In the hFSHr, specificity would be exerted both by the ectodomain and the serpentine portion.

MtDNA variation in the Altai-Kizhi population of southern Siberia: a synthesis of genetic variation.

The native peoples of Gorno Altai in southern Siberia represent a genetically diverse population and have been of great interest to anthropological genetics. In particular, the southern Altaian population is argued to be the best candidate for the New World ancestral population. In this study we sampled Altai-Kizhi from the southern Altaian village of Mendur-Sokkon, analyzed mtDNA RFLP markers and HVS-I sequences, and compared the results to other published mtDNA data from Derenko et al. (2003) and Shields et al. (1993) encompassing the same region. Because each independent study uses different sampling techniques in characterizing gene pools, in this paper we explore the accuracy and reliability of evolutionary studies on human populations. All the major Native American haplogroups (A, B, C, and D) were identified in the Mendur-Sokkon sample, including a single individual belonging to haplogroup X. The most common mtDNA lineages are C (35.7%) and D (13.3%), which is consistent with the haplogroup profiles of neighboring Siberian groups. The Mendur-Sokkon sample exhibits depressed HVS-I diversity values and neutrality test scores, which starkly differs from the Derenko et al. (2003) data set and more closely resembles the results for neighboring south Siberian groups. Furthermore, the multidimensional scaling plot of DA genetic distances does not cluster the Altai samples, showing different genetic affinities with various Asian groups. The findings underscore the importance of sampling strategy in the reconstruction of evolutionary history at the population level.

Molecular and temporal characteristics of human retropseudogenes.

One of the primary forces driving genome evolution is retrotranscription. In addition to creating new genetic material from which new genes with new functions arise, retrotranscription leaves traces of its action in the form of retropseudogenes. These loci, which are intronless, retrotransposed copies of mature mRNAs from functional antecedent genes, are layered throughout genomes as a molecular fossil record of genome evolution. A survey of 138 functional source genes in the human genome has revealed more than three hundred retropseudogenes. Analysis of the characteristics of the source genes shows that, on average, their size, G/C content, and expression patterns fit the canonical features of source genes reported elsewhere. Details of insertion site duplications for these loci are consistent with a model of retropseudogene formation involving endogenous retrotranscription and enzymatic mobilization and retroposition. Retrotranscription event age estimates reveal a pattern in which the highest densities appear after major phylogenetic events in primate history and then decline. This temporal pattern suggests that the processes forging genome evolution are most active during periods of speciation and adaptive radiation and then steadily diminish until the next burst of activity.

LOC 390443 (RNase 9) on chromosome 14q11.2 is related to the RNase A superfamily and contains a unique amino-terminal preproteinlike sequence.

A new member of the human RNase A superfamily is reported. Identified in the human genome assembly as LOC 390443, this locus is located 128 kb telomeric to the established RNase A gene family cluster on chromosome 14q11.2. The amino acid sequence of this locus is sufficiently similar to the eight previously identified gene family members to warrant a designation as RNase 9. RNase 9 is expressed in a wide range of human tissues. In addition, a 30-amino acid sequence lying between a 26-amino acid putative signal peptide and the last 148 amino acids that align with the other RNases A is not seen in other members of the RNase A superfamily in any species. Nucleotide and amino acid sequences of RNase 9 in 13 nonhuman primate species were determined and indicate several conserved sites but, also, an excess of nonsynonymous substitutions, about one-third of which are radical substitutions. This suggests that RNase 9, similar to several other human RNases A, has been under diversifying selection in the primates. Data from the mouse and rat genomes indicate that RNase 9 is also present in rodents, thus making it older than most of the established members of the human RNase A superfamily. Many of the human RNases A have been shown to have antimicrobial, antiviral, or antiparasitic functions involved in host-defense mechanisms. The features of RNase 9 described here suggest that it, too, may be involved in host defense and that it, along with the rest of the superfamily, may prove to have played an important role in anthropoid evolution.