Impairments of Photoreceptor Outer Segments Renewal and Phototransduction Due to a Peripherin Rare Haplotype Variant: Insights from Molecular Modeling

Background: Retinitis pigmentosa punctata albescens (RPA) is a particular form of retinitis pigmentosa characterized by childhood onset night blindness and areas of peripheral retinal atrophy. We investigated the genetic cause of RPA in a family consisting of two affected Egyptian brothers with healthy consanguineous parents. Methods: Mutational analysis of four RPA causative genes was realized by Sanger sequencing on both probands, and detected variants were subsequently genotyped in their parents. Afterwards, found variants were deeply, statistically, and in silico characterized to determine their possible effects and association with RPA. Results: Both brothers carry three missense PRPH2 variants in a homozygous condition (c.910C > A, c.929G > A, and c.1013A > C) and two promoter variants in RHO (c.-26A > G) and RLBP1 (c.-70G > A) genes, respectively. Haplotype analyses highlighted a PRPH2 rare haplotype variant (GAG), determining a possible alteration of PRPH2 binding with melanoregulin and other outer segment proteins, followed by photoreceptor outer segment instability. Furthermore, an altered balance of transcription factor binding sites, due to the presence of RHO and RLBP1 promoter variants, might determine a comprehensive downregulation of both genes, possibly altering the PRPH2 shared visual-related pathway. Conclusions: Despite several limitations, the study might be a relevant step towards detection of novel scenarios in RPA etiopathogenesis.

Morphological and Genetic Variability of the Mass Whitefish Forms in Lake Onega

In Lake Onega, the whitefish Coregonus lavaretus has been shown to occur as a variety of forms. Medium- and sparsely-ranked whitefish are most abundant. Analysis of available data indicates that whitefish populations from Karelia’s large lakes display the maximum values of various genetic variability indices. This fact seems to be due to the history of the colonization of the lake by the discrete evolutionary whitefish lineages from various Late Quaternary habitats followed by their hybridization. A great variety of Onega whitefish haplotypes is probably related to the genetic heterogeneity of the whitefish who until recently had occurred as five ecological forms ranking as subspecies. The median network obtained suggests that many of the populations studied have become less abundant. The well-defined “star-like” network structure is characteristic of populations that passed through a narrow “bottleneck” in the near past and then expanded rapidly, as indicated by the abundance of rare haplotype varieties. It seems that the retreat of the Scandinavian glacier was not a momentary event but took a long time during which the populations formed were subjected to demographic transformations.

Comparison of haplotype-based tests for detecting gene–environment interactions with rare variants

Dissecting the genetic mechanism underlying a complex disease hinges on discovering gene–environment interactions (GXE). However, detecting GXE is a challenging problem especially when the genetic variants under study are rare. Haplotype-based tests have several advantages over the so-called collapsing tests for detecting rare variants as highlighted in recent literature. Thus, it is of practical interest to compare haplotype-based tests for detecting GXE including the recent ones developed specifically for rare haplotypes. We compare the following methods: haplo.glm, hapassoc, HapReg, Bayesian hierarchical generalized linear model (BhGLM) and logistic Bayesian LASSO (LBL). We simulate data under different types of association scenarios and levels of gene–environment dependence. We find that when the type I error rates are controlled to be the same for all methods, LBL is the most powerful method for detecting GXE. We applied the methods to a lung cancer data set, in particular, in region 15q25.1 as it has been suggested in the literature that it interacts with smoking to affect the lung cancer susceptibility and that it is associated with smoking behavior. LBL and BhGLM were able to detect a rare haplotype–smoking interaction in this region. We also analyzed the sequence data from the Dallas Heart Study, a population-based multi-ethnic study. Specifically, we considered haplotype blocks in the gene ANGPTL4 for association with trait serum triglyceride and used ethnicity as a covariate. Only LBL found interactions of haplotypes with race (Hispanic). Thus, in general, LBL seems to be the best method for detecting GXE among the ones we studied here. Nonetheless, it requires the most computation time.

Complete mitochondrial genome sequences of rare haplotype E4 from Phu Quoc ridgeback dog

Phu Quoc ridgeback dog is an invaluable species in Vietnam. The discovery of high-frequency rare halophytes E4 and E1 in Phu Quoc ridgeback dog while evaluate analyzing its genetic distances is an unexpected event. In this research, the primer-walking strategy was used to sequence the whole mtDNA of Phu Quoc ridgeback dogs carrying E4, B1 and E1 halophytes to explore trace of Phu Quoc ridgeback dog's origin. These mtDNA’s length (16,760 bp for PQ1 and 16,731 for PQ2) fall into the range of 16.7 kb, particularly, 16.760 bp in E4 dogs and 16.731 bp in B1 dogs and is basically similar to the ones of other dog breeds. The difference in length between E4 and B1 haplotype is mainly due to the difference of motif repeat frequency in the control region. The number of genes, starting and ending codes of E4’s mtDNA are similar to other common halophytes. Genetic distances between Phu Quoc ridgeback dogs' E1, E4 haplotypes and Pungsan dogs (EU789662) in the same clade in the phylogenetic tree are 0,072% and 0,24%, respectively, showing that Phu Quoc dogs with E haplotypes are very close relatively to Pungsan dogs in North-Korea. Although belonging to the same haplogroup, the genetic distance between Phu Quoc dogs E1 and E4 haplotype is 0,23%. In the other hand, genetic distances between E1, E4 haplotypes Phu Quoc ridgeback dogs and the closest grey wolves on phylogenetic tree are 0,3% and 0,1%, respectively. This is the first mitochondrial genome of E4 haplotype dogs to be sequenced and analyzed.