A human derived SSADH coding variant is replacing the ancestral allele shared with primates

BACKGROUND: A growing number of reports describe markers with high frequencies of the ancestral alleles in Africa, contrasting with high frequencies and possibly fixation of derived variants out of Africa. Such a pattern can be explained by either neutral or non-neutral processes. AIM: The study examined worldwide frequencies of two non-synonymous variants in NAD(+)-dependent succinic semialdehyde dehydrogenase (SSADH), in a search for possible signatures of natural selection favouring the derived alleles. SUBJECTS AND METHODS: The typing of 1574 subjects were compiled, representing 60 populations from all continents. SSADH haplotype frequencies were correlated across 52 populations to those of 260 single nucleotide polymorphism (SNP) markers deposited in the CEPH database and of markers reported to be under positive Darwinian selection. RESULTS: In the world population, the c.538C variant is proceeding to replace the ancestral c.538T, shared with primates. The overall population differentiation is within the normal range. A significant correlation was also found between the frequencies of the derived alleles in SSADH and Microcephalin (MCPH1), which showed concerted changes worldwide and, at least in Asian populations, also on a restricted geographical scale. CONCLUSION: The analysis of robust correlations based on a large panel of populations is potentially able to identify clusters of genomic regions or genes showing co-evolution of the frequencies of derived alleles.     

A human derived SSADH coding variant is replacing the ancestral allele shared with primates

Background: A growing number of reports describe markers with high frequencies of the ancestral alleles in Africa, contrasting with high frequencies and possibly fixation of derived variants out of Africa. Such a pattern can be explained by either neutral or non-neutral processes.

Aim: The study examined worldwide frequencies of two non-synonymous variants in NAD⁺-dependent succinic semialdehyde dehydrogenase (SSADH), in a search for possible signatures of natural selection favouring the derived alleles.

Subjects and methods: The typing of 1574 subjects were compiled, representing 60 populations from all continents. SSADH haplotype frequencies were correlated across 52 populations to those of 260 single nucleotide polymorphism (SNP) markers deposited in the CEPH database and of markers reported to be under positive Darwinian selection.

Results: In the world population, the c.538C variant is proceeding to replace the ancestral c.538T, shared with primates. The overall population differentiation is within the normal range. A significant correlation was also found between the frequencies of the derived alleles in SSADH and Microcephalin (MCPH1), which showed concerted changes worldwide and, at least in Asian populations, also on a restricted geographical scale.

Conclusion: The analysis of robust correlations based on a large panel of populations is potentially able to identify clusters of genomic regions or genes showing co-evolution of the frequencies of derived alleles.     

A possible mechanism for maintenance of the deleterious allele of human CASPASE-12

In humans, a functional CASPASE-12 (CASP12) gene has been identified only in persons of African heritage and has been suggested to play a regulatory role in response to bacterial pathogens and in promoting and increased susceptibility to sepsis. The existence of a gene whose effect is deleterious, and which has been the subject of extensive negative selection in the rest of the human population, implies the simultaneous presence of some selective benefit for persons having CASP12. Given the importance of inflammatory immune responses in controlling the initial stages of infection, and the role that CASP12 plays in down-regulating inflammation, we hypothesize that pathogens which exploit the inflammatory response are restrained by an active CASP12 gene product. Several candidate pathogens are discussed.     

A possible new HLA-DR allele

In routine screening of anti-HLA DR reagents, serum 901 was obtained from a woman of negroid origin ten days after delivery of a second child. The spouse was also of black origin. This serum contained polyspecific HLA A and B antibodies. After platelet absorption it reacted with the B cells of 10 out of 119 European Caucasoid panel donors (8.4%) typed for DR1 to DRW10 and for MT1, MT2. Each of these ten donors had only one recognized DR antigen, the other was "blank." Serum 901 gave negative reactions with the homozygous typing cells (HTC) DW1 to DW8. In 18 normal informative Caucasoid families, serum 901 recognized one HLA haplotype in one (or both) parents and segregated with this haplotype in one or more than one child. In one family in which both parents reacted with serum 901, two children were homozygous for this marker and reacted as HTCs. One of these HTCs typed as DW9 and was found to be identical to a DW9.HTC (8W207).     

Olfactory receptor gene cluster on human chromosome 17: possible duplication of an ancestral receptor repertoire

A gene superfamily of olfactory receptors (ORs) has recentlybeen identified in a number of species. These receptors sharea seven transmembrane domain structure with many neurotransmitterand hormone receptors, and are likely to underlie the recognitionand G-protein-mediated transduction of odorant signals. Previously,OR genes cloned in different species were from random locationsin the respective genomes. We report here the cloning of 16human OR genes, all from chromosome 17(17p 13.3). The intronlesscoding regions are physically mapped (on 35 cosmids) in one0.35Mb long contiguous cluster, with an average intergenic separationof 15kb. The human OR genes in the cluster belong to four differentgene subfamilies, displaying as much sequence variability asany randomly selected group of ORs. This suggests that the clusteridentified may be one of several copies of an ancestral OR generepertoire whose existence may predate the divergence of mammals.The latter may have duplicated In some specles to form the presentmammalian OR gene repertoire, with several hundred genes. Thehuman chromosome 17 OR gene cluster may thus be a good modelfor understanding human olfeaction, as well as the ontogenyand phylogeny of the OR gene superfamlly.     

PTPN22 allele polymorphisms in 15 Chinese populations

Protein tyrosine phosphatase non‐receptor 22 (PTPN22) is involved in the negative regulation of T‐cell responsiveness. Recently, it has been reported that a single nucleotide polymorphism (SNP), C1858T, in the gene PTPN22, encoding Arg620Trp in the lymphoid protein tyrosine phosphatase (LYP), is associated with an increased risk of a number of autoimmune diseases. To study the mutant frequency and polymorphism of PTPN22 in Chinese populations, 1085 individuals from 15 Chinese populations distributing widely from north to south were collected. The genotypes of PTPN22‐C1858T were determined by polymerase chain reaction‐restriction fragment length polymorphism with the digestion of restriction endonuclease RsaI. Of the 1085 individuals, 31 of whom were heterozygote (PTPN22‐1858C/T), the frequency of PTPN22‐1858T allele in those tested individuals was 1.43%. Moreover, the frequencies of PTPN22‐1858T had significant variance in 15 populations of China (χ² = 74.1650, P < 0.01).     

Large sequence polymorphisms classify Mycobacterium tuberculosis strains with ancestral spoligotyping patterns

Genomic deletion analysis revealed that strains of Mycobacterium tuberculosis exhibiting spoligotyping patterns with almost all spacers present belong either to a strain lineage that includes the W-Beijing strain family or to the ancestral strain lineage of M. tuberculosis.     

CCR2 allele polymorphisms in 15 Chinese ethnic populations

Chemokine receptor-2 (CCR2) is a co-receptor for the entry of human immunodeficiency virus-1 (HIV-1) into the target cells. A mutation in CCR2 (CCR2-64I) exhibited a protective effect to delay the progression of acquired immunodeficiency syndrome (AIDS). To study the mutant frequency and polymorphism of CCR2 in Chinese populations, 1082 individuals from 15 Chinese populations distributing widely from north to south were collected. The genotypes of CCR2-64I were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) with the digestion of restriction endonuclease FokI. Of the 1082 individuals, 352 (32.53%) were carriers of CCR2-64I allele, 257 of whom (23.75%) were heterozygotes (CCR2-64V/I), whereas 95 (8.78%) were homozygotes (CCR2-64V/V). The frequency of the CCR2-64I allele in those tested individuals was 20.66%. This prevalence of CCR2-64I was higher than what was known for American and European populations. Moreover, the frequencies of CCR2-64I were generally higher in northern China than they were in southern China, and the frequencies had significant variance in 15 populations of China (chi2 = 27.135, P = 0.018).     

Apolipoprotein gene E4 allele promoter polymorphisms as risk factors for Alzheimer's disease

Alzheimer's disease is a complex neurodegenerative disorder, characterized by progressive cognitive decline and distinct neuropathology. The apolipoprotein gene E4 allele (APOE 4) is a major risk factor for the disease. Promoter polymorphisms at -491 and -427 may also contribute to the risk. We examined the two polymorphisms in 178 Alzheimer's patients and 141 controls. The -491AA genotype was overrepresented among the patients (68 versus 54%, P=0.01). However, in patients who were APOE4 carriers, the -491AA genotype more than doubled the risk [odds ratio (OR)=2.5; 95% confidence interval (CI)=1.2-5.4], especially in combination with -427TT [odds ratio (OR)=3.3; 95% confidence interval (CI)=1.5-7.7]. Moreover, the -491A/-427T/APOE4/APOC1A haplotype was threefold higher for patients. These results contribute to the evidence that regulation of APOE4 expression modulates risk for Alzheimer's disease.     

Determination of permethrin resistance allele frequency of human head louse populations by quantitative sequencing

A quantitative sequencing (QS) protocol that detects the frequencies of sodium channel mutations (M815I, T917I, and L920F) responsible for knockdown resistance in permethrin-resistant head lice (Pediculus humanus capitis De Geer) was tested as a population genotyping method for use as a preliminary resistance monitoring tool. Genomic DNA fragments of the sodium channel a-subunit gene that encompass the three mutation sites were polymerase chain reaction (PCR)-1 amplified from individual head lice with either resistant or susceptible genotypes, and combined in various ratios to generate standard DNA template mixtures for QS. After sequencing, the signal ratios between resistant and susceptible nucleotides were calculated and plotted against the corresponding resistance allele frequencies. Quadratic regression coefficients of the plots were close to 1, demonstrating that the signal ratios are highly correlated with the resistance allele frequencies. Resistance allele frequencies predicted by QS, using either "pooled DNA" (DNA extracted from individual louse specimens and pooled) or "pooled specimen DNA" (DNA simultaneously extracted from multiple louse specimens), agreed well with those determined by individual sequencing, confirming the reliability and accuracy of QS as a population genotyping method and validating our approach of using the pooled specimen DNA as the DNA template for QS. Our protocol for QS was determined to be highly reliable for the prediction of resistance allele frequencies higher than approximately 7.4% at the 95% confidence level. According to the resistance allele frequencies determined by QS, pyrethroid resistance varies substantially among different geographical regions, emphasizing the importance of early resistance detection and proper management strategies.     

Associations between restriction fragment length polymorphisms detected with a probe for human C4 and allotype of C4B5 allele

We studied the fourth component of human complement (C4) allotypes in 58 Japanese individuals. The technique of Southern, with C4 and 21-OH cDNA probes, was used to examine the genomic DNA of 45 individuals typed for C4 by protein electrophoresis. Novel HindIII C4 10- and 5-kb and EcoRI C4 13-Kb restriction fragments were identified in each of nine Japanese individuals. The novel fragments were different from the previously described C4B long (HindIII 31-kb, TaqI 6-kb, BamHI 4.3-kb, and EcoRI 12-kb) and C4B short (HindIII 25-kb, TaqI 5.4-kb, BamHI 3.5-kb, and EcoRI 15-kb) fragments. All novel HindIII- and EcoRI-positive individuals carried C4B5, BfS, and HLA-Bw54. Therefore, the fragments were characteristic for the C4B5 allele. The C4 region was analyzed to determine the restriction sites by single and double digests of uncloned genomic DNA with several restriction endonucleases. It is speculated that an insertion gene lies between the 3' end of the 21-OH and the 5' end of the C4B genes.     

Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis

Primary cutaneous amyloidosis (PCA) is an itchy skin disorder associated with amyloid deposits in the superficial dermis. The disease is relatively common in Southeast Asia and South America. Autosomal dominant PCA has been mapped earlier to 5p13.1–q11.2 and two pathogenic missense mutations in the OSMR gene, which encodes the interleukin-6 family cytokine receptor oncostatin M receptor beta (OSMRβ), were reported. Here, we investigated 29 Taiwanese pedigrees with PCA and found that 10 had heterozygous missense mutations in OSMR: p.D647V (one family), p.P694L (six families), and p.K697T (three families). The mutation p.P694L was associated with the same haplotype in five of six families and also detected in two sporadic cases of PCA. Of the other 19 pedigrees that lacked OSMR pathology, 8 mapped to the same locus on chromosome 5, which also contains the genes for 3 other interleukin-6 family cytokine receptors, including interleukin-31 receptor A (IL31RA), which can form a heterodimeric receptor with OSMRβ through interleukin-31 signaling. In one family, we identified a point mutation in the IL31RA gene, c.1562C>T that results in a missense mutation, p.S521F, which is also sited within a fibronectin type III-like repeat domain as observed in the OSMR mutations. PCA is a genetically heterogeneous disorder but our study shows that it can be caused by mutations in two biologically associated cytokine receptor genes located on chromosome 5. The identification of OSMR and IL31RA gene pathology provides an explanation of the high prevalence of PCA in Taiwan as well as new insight into disease pathophysiology.     

Serum ferritin as a possible marker of the hemochromatosis allele.

To determine whether a correlation exists between the biochemical expression of hemochromatosis and the HLA genotype, we studied 174 family members of 32 persons with the disease. Persons who shared both HLA haplotypes with the proband (and presumably having two hemochromatosis alleles) differed significantly from those who shared only one haplotype (and presumably having one hemochromatosis allele) in terms of serum iron (P less than 0.001 for both sexes), unsaturated iron-binding capacity (P less than 0.01 for female and P less than 0.0001 for male subjects) and serum ferritin (P less than 0.0001 for female and P less than 0.00001 for male subjects). The only significant difference between relatives having one hemochromatosis allele and age and sex-matched controls was related to serum ferritin values in male subjects (P less than 0.05, despite considerable overlap). In our hands, serum ferritin was the best indicator of disordered iron metabolism and was elevated among most homozygous but among few heterozygous family members.     

The genetics of placental alkaline phosphatase: a possible ''null'' allele

Data are presented on the placental alkaline phosphatase (Pl) phenotypes of 3655 placentae, including those from 1143 dizygotic twin pairs. Discrepancies are present between the observed numbers and those expected according to Hardy-Weinberg equilibrium, homozygotes being apparently in excess. This statistical discrepancy can be reduced to insignificance by proposing that the Pl system contains a ‘null’ allele, Pl⁰, in addition to the 17 alleles for which there is electrophoretic evidence. The plausibility of this suggestion is examined in the light of what is known about ‘null’ alleles in other enzyme systems and in other species.