Mendelian Prediction Research Articles

Data from electronic healthcare records expand our understanding of X-linked genetic diseases.

Disease specific cohort studies have reported details on X linked (XL) disorders affecting females. We investigated the spectrum and penetrance of XL disorders seen in electronic health records (EHR). We generated a cohort of individuals diagnosed with XL disorders at Vanderbilt University Medical Center over 20 years. Our cohort included 477 males and 203 females diagnosed with 108 different XL genetic disorders. We found large differences between the female/male (F/M) ratios for various XL disorders regardless of their OMIM annotated mode of inheritance. We identified four XL recessive disorders affecting women previously only described in men. Biomarkers for XL disease had unique gender-specific patterns differing between modes of inheritance. EHRs provide large cohorts of XL genetic disorders that give new insights compared to the literature. Differences in the F/M ratios and biomarkers of XL disorders observed likely result from disease specific and sex dependent penetrance. We conclude that observed gender ratios associated with specific XL disorders may be more useful than those predicted by Mendelian genetics provided by OMIM. Our findings of a gender specific penetrance and severity for XL disorders show unexpected differences from Mendelian predictions. Further work is required to validate our findings in larger combined EHR cohorts.

Global analysis of Plasmodium falciparum histidine-rich protein-2 (pfhrp2) and pfhrp3 gene deletions using whole-genome sequencing data and meta-analysis

Many rapid diagnostic tests (RDT) used on suspected malaria cases are based on the detection of the protein encoded by the Plasmodium falciparum histidine-rich protein-2 (pfhrp2) gene, which shares a high sequence homology with pfhrp3 in the 3D7 reference genome. Parasite isolates showing pfhrp2 and pfhrp3 gene deletions have been emerging over the years, but a comprehensive genetic analysis of these variants is still lacking. With this purpose, genomic data from experimental P. falciparum genetic crosses between different laboratory lines (3D7, HB3, DD2, 7G8 and GB4) were first analysed (n = 98). The frequency of pfhrp2 deletions was consistent with a Mendelian prediction in HB3 × DD2 (56.7%; 95%CI = (39.5%–72.9%)). Moreover, the pfhrp2 and pfhrp3 deletions segregated independently of each other in the same genetic cross. Analysis of 3D7 × HB3 and 7G8 × GB4 estimated the probability of spontaneously generating a pfhrp2 deletion during sexual recombination to be up to 6.2%. Next, whole genome sequence data from 1970 P. falciparum isolates collected globally were analysed. Nine samples displayed depth of coverage consistent with pfhrp2 deletions (0.5%), but the corresponding split-read analysis could not confirm deletions in seven of these samples. Twenty-eight isolates had evidence of pfhrp3 deletions (1.4%), which are widespread in Southeast Asia. Finally, a meta-analysis of published data revealed a positive mean association between the frequencies of pfhrp2 and pfhrp3 deletions in Africa and South America. This result suggested a shared selective pressure acting on these genetic variants. In conclusion, evidence of genetic selection on both pfhrp2 and pfhrp3 deletions was presented, but experimental crosses do not provide evidence of a fitness cost of these variants. Further work is urgently needed to accurately determine the prevalence and the degree of association between these genetic variants, and the respective impact on diagnostic accuracy of many in-use RDT.

Survival and Growth of C57BL/6J Mice Lacking the BK Channel (KCa1.1): Lower Adult Body Weight Occurs together with Higher Body Fat

The BK potassium channel contributes to K+ flow and the electrical behavior of many cell types: including pancreatic β‐cells and cells in the hypothalamic‐pituitary‐adrenal axis. Mice made null for the gene (Kcnma1, slo‐1) producing the BK channel exhibit numerous deficits in physiological functions, but also show resistance toward developing obesity on a high fat diet (Illison J, et al, Diabetes 2016 db160245). Initial breeding pairs lacking a single allele of Kcnma1 (BKhet) in a C57BL/6J background strain were obtained from Dr. Andrea Meredith at the University of Maryland. A colony derived by breeding these heterozygous mice had litter sizes of ~8 pups, 53% male. For the period of maternal care (P0 – P21) pup death peaked at P1 with a second less severe interval of pup death peaking near P13. The later deaths (~P13) of pups null for Kcnma1 (BKKO) were greater than Mendelian expectations. Pup death at ~P1 was twice as likely during the 20 month construction of a building adjacent to the animal facility compared with the quiescent period after cessation of construction. Births also were not consistent with Mendelian predictions, indicating a specific prenatal disadvantage for female BKKO mice in the quiescent period and for female BKhet mice during construction, a change likely induced by this environmental stressor. Death of colony mice after weaning was rare (~0.5%). After weaning, weight gain was lower for BKKO mice compared with wild‐type littermates: male BKKO mice were 5 g smaller and female BKKO mice were 4 g smaller. Lower weight gain for BKKO mice compared to wild‐type occurred in part due to an event of weight loss during the early post‐weaning period, between weeks 3 to 9. Interestingly, wild‐type mice as well as male BKKO mice were ~1 g larger during construction compared with mice during quiescence. Body composition determined by quantitative magnetic resonance (QMR) indicated a higher fat proportion for wild‐type female mice compared with males, as well as a higher hydration ratio (total water mass – free water mass/lean mass). Comparison of lean, fat, and water components for female and male mice suggested an interrelationship that governs changes to body composition. Both male and female BKKO mice showed higher fat proportions than wild‐type, with the female BKKO mice exhibiting a larger variation in fat content and male BKKO mice having a higher hydration ratio than wild‐type. Together these results indicate that BKKO mice suffered disadvantages that led to prenatal and perinatal death. A metabolic difference likely related to glucose handling led to the smaller body size and distinct composition with higher fat for BKKO mice, suggesting a diversion of energy supplies from growth to fat storage.Support or Funding Information[NIH DK65845; WSU‐BSoM Seed Grant]

Survival and growth of C57BL/6J mice lacking the BK channel, Kcnma1: lower adult body weight occurs together with higher body fat.

Big conductance potassium (BK) channels contribute to K+ flow and electrical behavior in many cell types. Mice made null for the gene (Kcnma1) producing the BK channel (BKKO) exhibit numerous deficits in physiological functions. Breeding mice lacking a single allele of Kcnma1 (C57BL/6J background) had litter sizes of approximately eight pups. For the period of maternal care (P0–P21), pup deaths peaked at P1 with a second less severe interval of death peaking near P13. Early deaths were twice as likely during a 20‐month period of building construction compared with the quiescent period after cessation of construction. Births during construction were not consistent with Mendelian predictions indicating the likelihood of a specific disadvantage induced by this environmental stressor. Later BKKO pup deaths (~P13) also were more numerous than Mendelian expectations. After weaning, weight gain was slower for BKKO mice compared with wild‐type littermates: 5 g less for male BKKO mice and 4 g less for female BKKO mice. Body composition determined by quantitative magnetic resonance indicated a higher fat proportion for wild‐type female mice compared with males, as well as a higher hydration ratio. Both male and female BKKO mice showed higher fat proportions than wild‐type, with female BKKO mice exhibiting greater variation. Together, these results indicate that BKKO mice suffered disadvantages that lead to prenatal and perinatal death. A metabolic difference likely related to glucose handling led to the smaller body size and distinct composition for BKKO mice, suggesting a diversion of energy supplies from growth to fat storage.

Impacts of early viability selection on management of inbreeding and genetic diversity in conservation.

Maintaining genetic diversity is a crucial goal of intensive management of threatened species, particularly for those populations that act as sources for translocation or re-introduction programmes. Most captive genetic management is based on pedigrees and a neutral theory of inheritance, an assumption that may be violated by selective forces operating in captivity. Here, we explore the conservation consequences of early viability selection: differential offspring survival that occurs prior to management or research observations, such as embryo deaths in utero. If early viability selection produces genotypic deviations from Mendelian predictions, it may undermine management strategies intended to minimize inbreeding and maintain genetic diversity. We use empirical examples to demonstrate that straightforward approaches, such as comparing litter sizes of inbred vs. noninbred breeding pairs, can be used to test whether early viability selection likely impacts estimates of inbreeding depression. We also show that comparing multilocus genotype data to pedigree predictions can reveal whether early viability selection drives systematic biases in genetic diversity, patterns that would not be detected using pedigree-based statistics alone. More sophisticated analysis combining genomewide molecular data with pedigree information will enable conservation scientists to test whether early viability selection drives deviations from neutrality across wide stretches of the genome, revealing whether this form of selection biases the pedigree-based statistics and inference upon which intensive management is based.

Constructing an initial map of transmission distortion based on high density HapMap SNPs across the human autosomes

Transmission distortion (TD) is a significant departure from Mendelian predictions of genes or chromosomes to offspring. While many biological processes have been implicated, there is still much to be understood about TD in humans. Here we present our findings from a genome-wide scan for evidence of TD using haplotype data of 60 trio families from the International HapMap Project. Fisher's exact test was applied to assess the extent of TD in 629,958 SNPs across the autosomes. Based on the empirical distribution of P(Fisher) and further permutation tests, we identified 1,205 outlier loci and 224 candidate genes with TD. Using the PANTHER gene ontology database, we found 19 categories of biological processes with an enrichment of candidate genes. In particular, the "protein phosphorylation" category contained the largest number of candidates in both HapMap samples. Further analysis uncovered an intriguing non-synonymous change in PPP1R12B, a gene related to protein phosphorylation, which appears to influence the allele transmission from male parents in the YRI (Yoruba from Ibadan, Nigeria) population. Our findings also indicate an ethnicity-related property of TD signatures in HapMap samples and provide new clues for our understanding of TD in humans.

Sex-restricted non-Mendelian inheritance of mouse chromosome 11 in the offspring of crosses between C57BL/6J and (C57BL/6J x DBA/2J)F1 mice.

We report on the observation of sex-restricted, non-Mendelian inheritance over a region of mouse Chromosome (Chr) 11, occurring in the offspring of crosses between two commonly used Mus musculus-derived inbred strains, C57BL/6J and DBA/2J. In the surviving backcross progeny of reciprocal matings between (C57BL/6J x DBA/2J)F1 hybrids and the C57BL/6J parental strain, we observed the preferential appearance of C57BL/6J alleles along a region of Chr 11. The deviation from Mendelian predictions was observed only in female offspring from both reciprocal backcrosses, and not in males from either cross. The sex-specificity of the observed non-Mendelian inheritance points to an explanation based on embryonic or neonatal lethality. Our data add to previously obtained evidence for a Chr 11 locus or loci with sex-specific and allele-specific effects on viability.

A Dwarf Mutant of Arabidopsis Generated by T-DNA Insertion Mutagenesis

Most plant genes that control complex traits of tissues, organs, and whole plants are uncharacterized. Plant height, structure of reproductive organs, seed development and germination, for example, are traits of great agronomic importance. However, in the absence of knowledge of the gene products, current molecular approaches to isolate these important genes are limited. Infection of germinatng seeds of Arabidopsis thaliana with Agrobacterium results in transformed lines in which the integrated T-DNA from Agrobacterium and its associated kanamycin-resistance trait cosegregate with stable, phenotypic alterations. A survey of 136 transformed lines produced plants segregating in a manner consistent with Mendelian predictions for phenotypes altered in height, flower structure, trichomes, gametogenesis, embryogenesis, and seedling development. This report is the characterization of a dwarf mutant in which the phenotype is inherited as a single recessive nuclear mutation that cosegregates with both the kanamycin-resistance trait and the T-DNA insert.

Diet termination for PKU: Yes or no?

To add to the confusion about phenylketonuria (PKU), there is a new wrinkle. According to a report published in March of this year in theProceedings of the National Academy of Sciences(75:1562), deficiency of the nonessential amino acid tyrosine may be just as responsible for the mental retardation in PKU as high levels of phenylalanine. A study by Samuel Bessman, MD, Malcolm Williamson, MD, and Richard Koch, MD, of the University of Southern California School of Medicine, attempted to correlate the mean IQ of siblings of known PKU children (67% of PKU siblings are heterozygous for PKU and 33% are normal, according to Mendelian predictions) with their ability to convert phenylalanine to tyrosine. Results showed a 10 point mean IQ difference between those siblings least able and those most able to convert phenylalanine to tyrosine. According to the investigators, since the mothers of PKU children are always heterozygous for