A global view of the OCA2-HERC2 region and pigmentation

Mutations in the gene OCA2 are responsible for oculocutaneous albinism type 2, but polymorphisms in and around OCA2 have also been associated with normal pigment variation. In Europeans, three haplotypes in the region have been shown to be associated with eye pigmentation and a missense SNP (rs1800407) has been associated with green/hazel eyes (Branicki et al. in Ann Hum Genet 73:160-170, 2009). In addition, a missense mutation (rs1800414) is a candidate for light skin pigmentation in East Asia (Yuasa et al. in Biochem Genet 45:535-542, 2007; Anno et al. in Int J Biol Sci 4, 2008). We have genotyped 3,432 individuals from 72 populations for 21 SNPs in the OCA2-HERC2 region including those previously associated with eye or skin pigmentation. We report that the blue-eye associated alleles at all three haplotypes were found at high frequencies in Europe; however, one is restricted to Europe and surrounding regions, while the other two are found at moderate to high frequencies throughout the world. We also observed that the derived allele of rs1800414 is essentially limited to East Asia where it is found at high frequencies. Long-range haplotype tests provide evidence of selection for the blue-eye allele at the three haplotyped systems but not for the green/hazel eye SNP allele. We also saw evidence of selection at the derived allele of rs1800414 in East Asia. Our data suggest that the haplotype restricted to Europe is the strongest marker for blue eyes globally and add further inferential evidence that the derived allele of rs1800414 is an East Asian skin pigmentation allele.     

Genetic mapping of the whirler mutation

The whirler (wi) mutation on mouse Chromosome (Chr) 4 results in an autosomal recessive neuroepithelial deafness and vestibular dysfunction exhibited as a characteristic shaker-waltzer behavior (deafness, circling, and head-bobbing). We have constructed a genetic linkage map across the wi region in both an interspecific [(wi/wi× CAST/Ei)F₁×wi/wi] backcross (n = 817) and an intraspecific [(wi/wi× CBA/Ca)F₁×wi/wi)] backcross (n = 335). In the interspecific backcross, wi was found to be non-recombinant with Orm1, 0.12 cM distal of D4Mit87 and Ambp, and 0.12 cM proximal of CD301. In the intraspecific backcross, wi was found to be non-recombinant with Orm1 and D4Mit244, 0.3 cM distal of Mup1, and 0.6 cM proximal of Tnc. We also report a family from the interspecific backcross that shows evidence of multiple recombinations across the region of mouse Chr 4 around the wi locus. These rearrangements appear specific to both the region and the family. Received: 10 July 1998 / Accepted: 19 January 1999     

Efficient localization of mutations by interval haplotype analysis

We have developed a mathematical algorithm to implement a method for localizing mutations using haplotype analysis. Our strategy infers haplotypes based on the determination of genotypes of a proximal and a distal marker for 21 chromosomal intervals distributed across the mouse genome (corresponding to two intervals for Chromosomes (Chrs) 1 and 2 and one for the remaining 17 autosomes). To simulate the analysis of mice homozygous for recessive mutations, we tested the efficacy of our method on over 200 data sets generated from two independent mapping panel data sets containing the genotypes of 46 F₂ progeny of an intercross and 94 F₂ progeny of a backcross. In all cases we were able to identify the chromosomal interval carrying the recessive mutation despite the fact that some of the data sets consisted of as few as 10 meioses. Our strategy proved sensitive and expedient, since the simulated genome-wide screen could be executed by genotype analysis of 40 microsatellite markers in small numbers of intercross or backcross progeny. Received: 2 June 1997 / Accepted: 22 October 1997     

A high-resolution map around the locus Om on mouse Chromosome 11

The locus Om (ovum mutant) identified in the mouse strain DDK affects the viability of (DDK |m~ non-DDK)F₁ preimplantation embryos. We previously located this locus on Chromosome (Chr) 11 close to Scya2 (Baldacci et al. Mamm. Genome 2, 100–105, 1992). Here we report a high-resolution map of the region around Om based on a large number of backcross individuals. The same region has been analyzed on the EUCIB backcross, and the two maps have been compared. The results define the proximal and distal boundaries for the Om mutation as Scya2 and D11Mit36 respectively. The distance between these two markers is about 2 cM. These data should facilitate the positional cloning and molecular characterization of Om. Received: 10 July 1995 / Accepted: 11 September 1995     

Quantitative trait loci affecting the difference in pigmentation between Drosophila yakuba and D. santomea

Using quantitative trait locus (QTL) mapping, we studied the genetic basis of the difference in pigmentation between two sister species of Drosophila: Drosophila yakuba, which, like other members of the D. melanogaster subgroup, shows heavy black pigmentation on the abdomen of males and females, and D. santomea, an endemic to the African island of S?o Tomé, which has virtually no pigmentation. Here we mapped four QTL with large effects on this interspecific difference in pigmentation: two on the X chromosome and one each on the second and third chromosomes. The same four QTL were detected in male hybrids in the backcrosses to both D. santomea and D. yakuba and in the female D. yakuba backcross hybrids. All four QTL exhibited strong epistatic interactions in male backcross hybrids, but only one pair of QTL interacted in females from the backcross to D. yabuka. All QTL from each species affected pigmentation in the same direction, consistent with adaptive evolution driven by directional natural selection. The regions delimited by the QTL included many positional candidate loci in the pigmentation pathway, including genes affecting catecholamine biosynthesis, melanization of the cuticle, and many additional pleiotropic effects.     

Evidence of a third locus in X-linked recessive spastic paraplegia

We have investigated a family with severe X-linked spastic paraplegia and assigned the disease locus to Xq11.2-q23 by linkage and haplotype analysis. This region harbors the gene coding for proteolipid protein, which is mutated in one of the two established forms of X-linked spastic paraplegia, i.e., SPG2. We have performed extensive mutation analysis of this gene. Our failure to detect a mutation in this family suggests a third locus in X-linked recessive spastic paraplegia. Received: 7 March 1997 / Accepted: 14 April 1997     

Estimating regional population size and annual harvest intensity of the sooty shearwater in New Zealand

Abstract

Recent comprehensive survey data from multiple New Zealand offshore islands were combined with demographic population models to produce the first formal estimate of the total population of sooty shearwaters within New Zealand territory. We estimated the total population over 1994–2005 to be 21.3 (19.0–23.6) million individual birds in the New Zealand region. This population consisted of 12.8 (12.0–13.6) million adults, 2.8 (2.5–3.1) million chicks, and 4.4 (4.2–4.7) million breeding pairs. Breeding sooty shearwaters were concentrated primarily around the southern islands of New Zealand, with 53% breeding in the Titi Islands surrounding Rakiura (Stewart Island). Rakiura Maori muttonbirders were estimated to harvest 360 000 (320 000–400 000) sooty shearwaters per year, equivalent to 18% of the chicks produced in the harvested areas and 13% of chicks in the New Zealand region. Overall, 11% of the chicks within the Titi Islands live on unharvested ground. Systematic and widespread surveys of breeding colonies in South America are needed before a reliable global sooty shearwater population estimate can be calculated.     

The hypotrichosis-generating shorn (shn) mutation maps to distal chromosome 7 in the Norway rat

We have recently identified an autosomal recessive mutation in the Norway rat that generates an almost complete absence of normal hair. Here we describe a multilocus backcross analysis that was used to map this mutation, named shorn (gene symbol shn), to the distal end of rat chromosome 7. Although this region in rat carries no previously mapped similar mutations, the homologous genomic regions in mouse and human contain several potential homologues and candidate genes.     

Identification of random amplified polymorphic DNA (RAPD) markers linked to the v locus in barley, Hordeum vulgare L.

 Recombinant backcross lines of barley were produced from a cross between Kanto Nakate Gold (KNG; two-rowed) and Azumamugi (AZ; six-rowed) after backcrosses of F₁ plants with AZ as the recurrent parent. Each of these lines had an introgressed segment from chromosome 2 of KNG. Two recombinant backcross lines, L1 and M3-13, were used for an initial screening of polymorphism. After screening a total of 888 oligonucleotides as arbitrary primers, we identified eight random amplified polymorphic DNAs (RAPDs) between backcross lines and AZ. Among the RAPD fragments, CMNA-38₇₀₀ was linked to the v locus with a recombination frequency of zero, while OPJ-09₈₅₀ and OPP-02₇₀₀ were linked to the v locus at a map distance of 1.4 cM. Thus, the three RAPD markers were clustered around the v locus since the lengths of introgressed chromosomal segments in the L1 and M3-13 lines were no less than 38 cM. The other five RAPD fragments that we identified were not linked to the v locus. Received: 14 January 1997 / Accepted: 14 February 1997     

A high-frequency null mutant of an odorant-binding protein gene, Obp57e, in Drosophila melanogaster

We have found a null mutant of an odorant-binding protein, Obp57e, in Drosophila melanogaster. This frameshift mutation, which is a 10-bp deletion in the coding region, is at a high frequency in the Kyoto population and is also present in Taiwan and Africa. We have sequenced a 1.5-kb region including the tandemly duplicated gene, Obp57d, from 16 inbred lines sampled in Kyoto, Japan. The analyses showed a peak of nucleotide diversity and strong linkage disequilibrium around this mutation. This pattern suggests an elevated mutation rate or an influence of balancing selection in this region. The level of nucleotide divergence between D. melanogaster and D. simulans does not support the former possibility. Thus, this presence/absence polymorphism may be due to balancing selection, which takes advantage of the relatively weak functional constraint in members of a large gene family. In addition, the Obp57d gene region showed an excess of high-frequency-derived mutants that is consistent with a pattern predicted under positive natural selection.     

Dorsal patterning defects in the hindbrain, roof plate and skeleton in the dreher (dr(J)) mouse mutant

dreher is a spontaneous mouse mutation in which adult animals display a complex phenotype associated with hearing loss, neurological, pigmentation and skeletal abnormalities. During early embryogenesis, the neural tube of dreher mutants is abnormally shaped in the region of the rhomboencephalon, due to problems in the formation of a proper roof plate over the otic hindbrain. We have studied the expression of Hox/lacZ transgenic mouse strains in the dreher background and shown that primary segmentation of the neural tube is not altered in these mutants, although correct morphogenesis is affected resulting in misshapen rhombomeres. Neural crest derivatives from rhombomere 6, such as the glossopharyngeal ganglion, are defective, and the dorsal neural tube marker Wnt1 is absent from this segment. Selected trunk neural crest populations are also altered, as there is a lack of pigmentation in the thoracic region of mutant mice. Skeletal defects include abnormal cranial bones of neural crest origin, and improper fusion of the dorsal aspects of cervical and thoracic vertebrae. Taken together, the gene affected in the dreher mutant is responsible for correct patterning of the dorsal-most cell types of the neural tube, that is, the neural crest and the roof plate, in the hindbrain region. Axial skeletal defects could reflect inductive influence of the dorsal neural tube on proper fusion of the neural arches. It is possible that a common precursor population for both neural crest and roof plate is the cellular target of the dreher mutation.     

Genetic and immunohistochemical detection of mutations inactivating the keratinocyte transglutaminase in patients with lamellar ichthyosis

Autosomal recessive lamellar ichthyosis is a clinically heterogeneous group of severe congenital keratinization disorders that is characterized by generalized hyperkeratosis and variable erythema. About half of the patients have mutations in the TGM1 gene, which encodes the keratinocyte transglutaminase. Linkage studies have shown that at least two further loci for autosomal recessive lamellar ichthyosis must exist. We present here two patients with lamellar ichthyosis caused by mutations in the TGM1 gene. The first patient is compound heterozygous for the novel missense mutation C53S and the splice mutation A3447G. The second patient, a child of consanguineous parents from Tunisia, is homozygous for the unknown nonsense mutation W263X. This is the first report of a mutation, C53S, that affects the region of the keratinocyte transglutaminase that is essential for anchorage of the enzyme to the plasma membrane. A novel, rapid in situ transglutaminase activity assay revealed the absence of keratinocyte transglutaminase activity in both patients. The mutations described are hence causative for the ichthyosis phenotype. Received: 27 October 1997 / Accepted: 24 November 1997     

A high-resolution genetic map around waltzer on mouse Chromosome 10 and identification of a new allele of waltzer

A new autosomal recessive mouse mutation characterized by deafness and circling behavior was recovered during mutagenesis experiments with chlorambucil (CHL). On the basis of allelism tests and linkage analyses, this mutation appears to represent a new allele of waltzer (v) that maps to mouse Chromosome (Chr) 10. We have designated this new allele, Albany waltzer (v ^Alb ). A high-resolution map of the region around v was constructed from data from two intersubspecific backcrosses involving Mus musculus castaneus. The analysis of 648 backcross mice has allowed v ^Alb to be localized 1.1 ± 0.4 cM distal to D10Mit60 and 0.2 ± 0.2 cM proximal to a cluster of four markers, D10Mit172, D10Mit112, D10Mit48, and D10Mit196. An independent backcross was used to confirm the map order and distances in the v ^Alb backcross. The two linkage maps were consistent, indicating that the lesion in v ^Alb , which is presumed to be a deletion based on the known action of CHL, is small and has not significantly altered the map at this level of detection. Additionally, three genes (Ros1, Grik2, and Zfa) were eliminated as possible candidates for v ^Alb , and several SSLP markers were separated genetically. Received: 3 July 1996 / Accepted: 13 August 1996     

A natural mutation in rc reverts white-rice-pericarp to red and results in a new, dominant, wild-type allele: Rc-g

The Rc locus regulates pigmentation of the rice bran layer, and selection for the rc allele (white pericarp) occurred during domestication of the crop. White bran is now ubiquitous among cultivated varieties throughout rice growing regions of the world. We identified a new allele that arose by natural mutation within the rc pseudogene of the cultivar 'Wells'. The mutation restored the reading frame of the gene, and reverted the bran layer pigmentation to red (wild-type). By sequencing the Rc locus in plants derived from red seeds, and linkage analysis in a segregating population, we were able to demonstrate that mutation within rc resulted in the new, dominant, wild-type allele Rc-g.     

Phylogenetic Analysis of Enterovirus 71 Strains Isolated during Linked Epidemics in Malaysia, Singapore, and Western Australia

Enterovirus 71 (EV71) is a frequent cause of hand, foot, and mouth disease (HFMD) epidemics associated with severe neurological sequelae in a small proportion of cases. There has been a significant increase in EV71 epidemic activity throughout the Asia-Pacific region since 1997. Recent HFMD epidemics in this region have been associated with a severe form of brainstem encephalitis associated with pulmonary edema and high case fatality rates. In this study, we show that four genetic lineages of EV71 have been prevalent in the Asia-Pacific region since 1997, including two previously undescribed genogroups (B3 and B4). Furthermore, we show that viruses belonging to genogroups B3 and B4 have circulated endemically in Southeast Asia during this period and have been the primary cause of several large HFMD or encephalitis epidemics in Malaysia, Singapore, and Western Australia.     

Distribution of an allele associated with blond hair color across northern island melanesia

Pigmentation of the skin, hair, and eyes is a complex trait controlled by multiple genetic loci. Recently a non‐synonymous mutation in the pigmentation candidate gene TYRP1 was shown to be significantly associated with a blond‐hair phenotype in populations from the Solomon Islands. The distribution of this mutation in the islands of Northern Island Melanesia, where the blondism phenotype is also prevalent, was unknown. Here, we present data describing the distribution of this allele in 550 individuals sampled from across this region, and test for associations between genotype at this locus and quantitatively measured skin and hair pigmentation phenotype. We report that the frequency of the 93C allele is notably lower than observed in the Solomons (0.12 vs. 0.26). The allele exhibits significant geographic heterogeneity across the islands sampled (χ² = 108.4, P < 0.0001). It is observed at its highest frequencies on the islands of New Ireland and New Hanover, while being almost completely absent from the large island of New Britain. Using linear regression with age, sex, and island as covariates we report that, as in the Solomons, the 93C allele is significantly associated with a decrease in hair pigmentation but not skin pigmentation. We discuss the distribution of the 93C allele across the Southwest Pacific in light of its possible place of origin and dispersal. Am J Phys Anthropol 153:653–662, 2014. © 2014 Wiley Periodicals, Inc.     

A novel missense mutation (S18N) in the 5′ non-HMG box region of the SRY gene in a patient with partial gonadal dysgenesis and his normal male relatives

Mutations in the sex-determining region of the Y chromosome (the SRY gene) have been reported in low frequency in patients with 46,XY gonadal dysgenesis. We investigated 21 Brazilian 46,XY sex-reversed patients, who presented either complete or partial gonadal dysgenesis or embryonic testicular regression syndrome. Using Southern blotting, polymerase chain reaction, denaturing gradient gel electrophoresis and direct sequencing, we analyzed deletions and point mutations in the SRY gene. We found a missense mutation at codon 18 upstream of the 5′ border of the HMG box of the SRY gene in one patient with partial gonadal dysgenesis. This variant sequence was also found in DNA obtained from blood and sperm cells of his father and in blood cells of his normal brother. The S18N mutation was not found in 50 normal males, ruling out the possibility of a common polymorphism. We identified a novel familial missense mutation (S18N) in the 5’ non-HMG box of the SRY gene in 1 of 21 patients with 46,XY sex reversal. Received: 6 May 1997 / Accepted: 2 October 1997