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 Y-associated allele is shared among a few ethnic groups of Asia

Summary In our previous study, both of Y-associated alleles, Y1 and Y2, were detected in Japanese and Koreans, but only the Y1 allele was detected in each of other populations including Chinese in both Beijin and Guangzhou areas, Caucasians, Africans, and Jewish. In the present study, these observations were extended to other ethnic groups in East Asia. Evenks in central Siberia and Khalkhs in Mongolia had only the Y1 allele. On the other hand, two ethnic groups, Fo-lo and Hakka, in Taiwan had both of the Y1 and the Y2 alleles. Three of the eight Y2-positive men, 2 Fo-lo and a Hakka, shared family name Chen. Both Hakka people and ancesters of Chen families could be traced to the Province of Henan in northern China in early 4th century. They arrive din Fujian/Guangdong area in the south-east Chinavia various routes and then some of them migrated to Taiwan in the 18th century. It is tempting to speculate that the Y2 allele may be originated from an ancestral population in Henan from which, Japanese, Koreans, and some of the Taiwanese diverged.     

A variant of human cytomegalovirus derived from a persistently infected culture

Infection of cells derived from an osteogenic sarcoma (HOS) with human cytomegalovirus (HCMV) resulted in persistent infection. It appears that persistent infection is due to a balance between release of virus and the growth of uninfected cells. Viruses derived from the persistently infected cultures were not temperature sensitive nor were they defective interfering particles. However, hybridization experiments using the Q-labeled probe from the XbaI Q fragment indicated that one copy of the repeat sequences contained in fragments Q and O of CMV, Towne DNA have been completely deleted from the virus DNA derived from the persistent culture. Thus the mechanism of persistent infection is probably due in part to a variant of CMV present in the cultures.     

Mhc-E polymorphism in Pongidae primates: the same allele is found in two different species

Mhc-E intron 1, exon 2, intron 2, and exon 3 from pygmy chimpanzee (Pan paniscus) , chimpanzee (Pan troglodytes) , gorilla (Gorilla gorilla) and orangutan (Pongo pygmaeus) have been sequenced; six new Mhc-E alleles have been obtained but sequence changes are only placed either in introns or in synonymous exonic bases. One pygmy chimpanzee Mhc-E DNA sequence is identical to another sequence from chimpanzee; the fact that no variation is found also at the intronic level suggests that these two species of chimpanzee may have recently separated and/or that both of them might only represent subspecies. Mhc-E phylogenetic trees separate two evolutionary groups: Pongidae , including humans, and Cercopithecinae ; this is also found by studying another non-classical class I gene, Mhc-G. The Mhc-E alleles' invariance at the protein level supports that strong selective forces are operating at the Mhc-E locus, as has also been found in both Cercopithecinae and humans. These allelic and evolutionary data suggest an altogether different functionality for HLA-E (and also HLA-G ) compared with classical class I proteins: i.e., sending negative (tolerogenic) signals to NK and T cells.     

A polymorphic variant of the gene coding desmoglein 1, the target autoantigen of pemphigus foliaceus, is associated with the disease

Two polymorphic markers were identified on the desmoglein 1 gene which encodes the autoantigen targeted by pathogenic antibodies in pemphigus foliaceus (PF), a cutaneous autoimmune blistering disease. The first marker, made of a variant haplotype of five mis-sense mutations located on the part of the gene encoding the fourth and fifth extracellular domains of the protein, is not associated with the disease. The second marker consists of a single silent T to C transition at position 809 and was found to be significantly more frequent (P = 0.015) in Caucasian PF patients (n = 36) than in controls (n = 98). Thus, pemphigus foliaceus constitutes another example of autoimmune disease in which the autoantigen polymorphism contributes to disease susceptibility.     

A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy

Intraflagellar transport (IFT) is vital for the functioning of primary cilia. Defects in several components of IFT complexes cause a spectrum of ciliopathies with variable involvement of skeleton, brain, eyes, ectoderm and kidneys. We examined a child from a consanguineous family who had short stature, narrow thorax, short hands and feet, postaxial polydactyly of hands, pigmentary retinopathy, small teeth and skeletal dysplasia. The clinical phenotype of the child shows significant overlap with cranioectodermal dysplasia type I (Sensenbrenner syndrome). Whole‐exome sequencing revealed a homozygous nonsense variant p.R142* in IFT52 encoding an IFT‐B core complex protein as the probable cause of her condition. This is the first report of a human disease associated with IFT52.     

A haplotype encompassing the variant allele of DNA repair gene polymorphism ERCC2/XPD Lys751Gln but not the variant allele of Asp312Asn is associated with risk of lung cancer in a northeastern Chinese population

The effect of the polymorphism of the DNA repair gene ERCC2/XPD Asp312Asn on the risk of lung cancer was investigated in a northeastern Chinese population. A hospital-based case-control study consisted of 201 lung cancer cases and 171 cancer-free controls matched to age, sex, and ethnicity. A polymerase chain reaction-restriction fragment length polymorphism method was used for genotyping. Frequency of the variant C-allele of ERCC2 Asp312Asn was 0.006 among the controls in present study, which differs markedly from previous reports both in European ancestry populations and in other Chinese populations (all P < 0.001). The polymorphism was not associated with risk of lung cancer. Haplotype analysis including three previously studied polymorphisms (ERCC1 Asn118Asn, ERCC2 Arg156Arg, and ERCC2 Lys751Gln) revealed that a haplotype consisting of ERCC1Asn118Asn(G)-ERCC2 Arg156Arg(C)-ERCC2 Asp312Asn(G)-ERCC2 Lys751Gln(C) was marginally associated with an increased risk of lung cancer (OR = 3.61, 95% CI = 1.00-13.06, P = 0.04). Our data suggest that the polymorphism ERCC2 Lys751Gln or a haplotype encompassing the variant allele is associated with risk of lung cancer in this population. Studies including larger sample sizes are needed to elucidate the effects of these polymorphisms on lung cancer risk in this northeastern Chinese population.     

A frequent allele codes for a truncated variant of semenogelin I,the major protein component of human semen coagulum

Human semen coagulum predominantly consists of high molecular mass complexes of the seminal vesicle secreted semenogelin I (SgI) and semenogelin II (SgII). Here we describe a previously unknown variant of the SgI gene that is present at an allele frequency of approximately 3% in the Swedish population. It gives rise to a protein with a molecular mass of 43 kDa, SgI(43), which compared with the 50 kDa variant, SgI(50), is lacking a tandem repeat of 60 amino acid residues that was probably deleted by homologous recombination. In spite of the size difference, SgI(43) has many properties in common with SgI(50), such as a very high iso-electric point and susceptibility to proteolytic degradation by prostate-specific antigen. Heterozygous carriers of the SgI(43) allele neither show impaired fertility nor do they significantly differ from individuals homozygous for SgI(50) with respect to sperm parameters such as semen volume, sperm count and fraction of motile spermatozoa.     

A DQA1 allele is strongly associated with idiopathic membranous nephropathy

The high molecular weight genomic DNA from 31 patients with idiopathic membranous nephropathy (IMN) has been digested with a restriction endonuclease Taq I, electrophoresed, blotted and hybridised with probes to the HLA-DRB, -DQA, -DQB, -DPA and -DPB genes. The restriction endonuclease Msp I was also used with the HLA-DPA and -DPB probes. The resulting restriction fragment length polymorphism (RFLP) has been analysed and compared with 55 controls treated in the same way. There was a significant increase in the DRB restriction fragments associated with HLA-DR3 (Fisher's p = 0.011), in particular with a sub-division of DR3 (Fisher's p = 0.0038). These results confirm at the DNA level serological correlations observed for IMN. A 4.5 Kb DQA RFLP was significantly raised in IMN patients (Fisher's p = 0.002) and is proposed as a major disease susceptibility factor.     

A novel cis-AB allele derived from the A transferase gene by nucleotide substitution C796A

The cis-AB is a very rare phenotype in the ABO blood group system. It corresponds to a special ABO allele encoding a glycosyltransferase that is capable of synthesizing both A and B antigens. Until now, gene sequences of only 3 cis-AB alleles were characterized. One was the A(1v) allele with a nucleotide substitution G803C at codon 268; the second was the B allele with a nucleotide substitution A796C at codon 266; and the third arose from a point mutation C700T at codon 234 in exon 7 of the B transferase gene. In this study, we found a novel cis-AB allele when performing paternity tests in Chang Gung Memorial Hospital in Taiwan. Although his father was O blood type, a serologically AB blood type child was confirmed as being his father's offspring on the basis of 16 microsatellite markers (99.97% plausibility for the child and father). Exons 6 and 7 of the child's ABO alleles were characterized by direct sequencing and gene cloning. The results showed that the child has one O(1) allele and the second allele is almost identical to A(1*02) allele except for a single point mutation at nucleotide position 796, where an A replaces a C and leads to a change of leucine to methionine at amino acid 266. This implies that the child's O(1) allele was inherited from his father and the other allele was inherited from his mother. In conclusion, the novel cis-AB allele reported here is derived from the A transferase gene through a nucleotide substitution C796A, which differs from the 3 previously reported cis-AB alleles.     

A luteinizing hormone receptor intronic variant is significantly associated with decreased risk of Alzheimer's disease in males carrying an apolipoprotein E ε4 allele

Genetic and biochemical studies support the apolipoprotein E (APOE) ε4 allele as a major risk factor for late-onset Alzheimer's disease (AD), though ~50% of AD patients do not carry the allele. APOE transports cholesterol for luteinizing hormone (LH)-regulated steroidogenesis, and both LH and neurosteroids have been implicated in the etiology of AD. Since polymorphisms of LH beta-subunit (LHB) and its receptor (LHCGR) have not been tested for their association with AD, we scored AD and age-matched control samples for APOE genotype and 14 polymorphisms of LHB and LHCGR. Thirteen gene-gene interactions between the loci of LHB, LHCGR, and APOE were associated with AD. The most strongly supported of these interactions was between an LHCGR intronic polymorphism (rs4073366; lhcgr2) and APOE in males, which was detected using all three interaction analyses: linkage disequilibrium, multi-dimensionality reduction, and logistic regression. While the APOE ε4 allele carried significant risk of AD in males [p = 0.007, odds ratio (OR) = 3.08(95%confidence interval: 1.37, 6.91)], ε4-positive males carrying 1 or 2 C-alleles at lhcgr2 exhibited significantly decreased risk of AD [OR = 0.06(0.01, 0.38); p = 0.003]. This suggests that the lhcgr2 C-allele or a closely linked locus greatly reduces the risk of AD in males carrying an APOE ε4 allele. The reversal of risk embodied in this interaction powerfully supports the importance of considering the role gene-gene interactions play in the etiology of complex biological diseases and demonstrates the importance of using multiple analytic methods to detect well-supported gene-gene interactions.     

The D allele of the ACE I/D common gene variant is associated with Type 2 diabetes mellitus in Caucasian subjects

The deletion D allele of the angiotensin-I converting enzyme (ACE) I/D gene variant is associated with higher ACE activity in Caucasians and previous studies in non-Caucasian samples have suggested an association between the D allele and type 2 diabetes (Type 2DM). The aim of this study was to compare the genotype distribution between Caucasian subjects with Type 2DM and non-diabetic Caucasian men. Genotype distribution was compared between 574 Caucasian subjects with Type 2DM, recruited from the UCL Diabetes and Cardiovascular Disease Study and 2413 non-diabetic Caucasian men, recruited from the second Northwick Park Heart Study. Within both samples, genotype distributions were in Hardy-Weinberg equilibrium. The genotype distributions in those with Type 2DM compared to the non-diabetic men (II/ID/DD) was 18%/50%/32% vs. 23%/49%/27%, p=0.004. In accordance with this, the frequency of the D allele was higher in those with Type 2DM (0.574 [0.55-0.60] vs. 0.519 [0.50-0.53], p=0.001). On combining the two samples, the odds ratio (OR) for Type 2DM was significantly higher in D allele carriers compared to II subjects (OR=1.55, p=0.02, after adjustment for age, sex, BMI, blood pressure, and lipids). In those with diabetes, there was a significant association between genotype and a family history of diabetes. The odds ratio for a family history of diabetes in DD compared to II subjects was 1.52 [0.89-2.60], p=0.03. This study clearly shows an association between the ACE I/D common gene variant and Type 2DM.     

A novel genetic variant in the apolipoprotein A5 gene is associated with hypertriglyceridemia

The apolipoprotein A5 gene (APOA5 ) has been shown to play an important role in determining plasma triglyceride concentrations in humans. We describe here a novel variant, c.553G>T, in the apolipoprotein A5 gene that is associated with hypertriglyceridemia. In contrast to some other polymorphisms, which occur in non-coding regions of the gene, this variant occurs within the coding region and causes the change of amino acid sequence (a substitution of a cysteine for a glycine residue). The minor allele frequencies were 0.042 and 0.27 (P<0.001) for control and hypertriglyceridemic patients, respectively. The serum triglyceride level was significantly different among the genotypic groups (G/G 92.5+/-37.8 mg/dl, G/T 106.6+/-34.8 mg/dl, T/T 183.0 mg/dl, P=0.014) in control subjects. Multiple logistic regression revealed individuals carrying the minor allele had age, gender and BMI (body mass index)-adjusted odds ratio of 11.73 (95% confidence interval of 6.617-20.793; P<0.0001) for developing hypertriglyceridemia in comparison to individuals without that allele. These findings suggest the possible use of c.553G>T polymorphisms in APOA5 as prognostic indicators for hypertriglyceridemia susceptibility in Chinese.     

A structural variant of the human interferon-gamma gene

The first structural IFNG variant, G54D (c.287G>A, ss105106770), located in the second exon, was identified.     

Lack of association of SDF-1 3'A variant allele with long-term nonprogressive HIV-1 infection is extended beyond 16 years

We studied the frequency of the SDF-1 3'A allelic variant (801G-->A) in a cohort of white Spaniards made up of (1) HIV-1-infected long-term nonprogressors (LTNPs) older than 16 years of age (n = 57), (2) HIV-1-infected usual progressors (UPs; n = 107), and (3) a group of healthy controls (n = 100). The mutant SDF-1 3'A allele was observed in 28% of LTNPs, 19% of UPs, and 26% of healthy controls (P = not significant). Homozygosity for the 3'A mutation was detected in 7%, 4%, and 3% of LTNPs, UPs, and healthy controls, respectively (P = not significant). Polymorphism at the SDF-1 locus is not associated with LTNP disease of longer than 16 years in Spanish HIV-1-infected patients. This effect is independent of the CCR5Delta32 allele.     

A pyrogen derived from human white cells which is active in mice.

An endogenous pyrogen smaller in molecular size than that previously obtained from human white cells has been found in supernatants of these cells after uptake of zymosan and incubation for 18 h. The new pyrogen after separation from other pyrogens which are produced at the same time has been found to produce fever in mice but not in rabbits. Because it is not formed if cycloheximide is present and is inactivated by leucine aminopeptidase, it is believed to be a peptide.     

A functional variant of IFNgamma gene is associated with coeliac disease

In coeliac disease (CD) a profile of proinflammatory cytokines are secreted interferon gamma (IFNgamma) being one of the most important. A dinucleotide polymorphism consisting of a variable number of CA repeats related with IFNgamma production levels, has been reported on the first intron of the IFNgamma gene. The aim of this study was to analyse the influence of the functional IFNgamma CA repeats in CD predisposition through familial and case-control studies. The familial analysis showed that the 124 bp allele was significantly more transmitted to the affected offspring (P=0.02), while the 126 bp allele showed a statistically significant nontransmission pattern (P=0.01). Nevertheless, in the case-control analysis, we could not find a direct association of CA repeats with CD. This fact might be due to parent-of-origin effect in the IFNgamma CA polymorphism. Our data suggest a possible role of IFNgamma CA polymorphism in CD susceptibility.