Unique Inheritance Pattern Research Articles

Enrichment of Hard Sweeps on the X Chromosome in Drosophila melanogaster.

The characteristic properties of the X chromosome, such as male hemizygosity and its unique inheritance pattern, expose it to natural selection in a way that can be different from the autosomes. Here, we investigate the differences in the tempo and mode of adaptation on the X chromosome and autosomes in a population of Drosophila melanogaster. Specifically, we test the hypothesis that due to hemizygosity and a lower effective population size on the X, the relative proportion of hard sweeps, which are expected when adaptation is gradual, compared with soft sweeps, which are expected when adaptation is rapid, is greater on the X than on the autosomes. We quantify the incidence of hard versus soft sweeps in North American D. melanogaster population genomic data with haplotype homozygosity statistics and find an enrichment of the proportion of hard versus soft sweeps on the X chromosome compared with the autosomes, confirming predictions we make from simulations. Understanding these differences may enable a deeper understanding of how important phenotypes arise as well as the impact of fundamental evolutionary parameters on adaptation, such as dominance, sex-specific selection, and sex-biased demography.

Development and validation of a new 18 X-STR typing assay for forensic applications.

With a unique inheritance pattern compared to autosomal short tandem repeats (A-STRs), X chromosomal STRs (X-STRs) have special usage in forensic relationship testing. In this study, we designed a multiplex amplification system (named TYPER-X19 multiplex assay) consisting of 18 STR loci spreading from 7.837 to 149.460 Mb on the X chromosomes (DXS9895, DXS8378, DXS9902, DXS6810, DXS7132, DXS10079, DXS6789, DXS7424, DXS101, DXS6797, DXS7133, DXS6804, GATA165B12, DXS10103, HPRTB, GATA31E08, DXS8377, and DXS7423), and the amelogenin. PCR primers were marked with four kinds of fluorophores including FAM, HEX, TAMRA, and ROX. The multiplex system was optimized and tested for precision, concordance, reproducibility, sensitivity, stability, DNA mixture, and species specificity according to the conventional validation guidelines. The results indicated that the system was accurate, reliable, and sensitive enough, and was suitable for common forensic case-type samples. In the population genetic study, a total of 148 alleles were detected at the 18 X-STR loci in 398 Southern Han Chinese. Relatively high combined power of discrimination in male (PDm ), power of discrimination in female (PDf ), mean paternity exclusion chance in trios (MECtrio ), and mean paternity exclusion chance in duos (MECDuo ) by Desmarais were detected, and HPRTB-DXS10103 was in linkage disequilibrium. The results suggested that the TYPER-X19 multiplex assay was suitable for forensic applications.

Fragile X Syndrome: Introduction.

Fragile X syndrome (FXS) is one of the most common reasons for intellectual disability (ID). First described in the 1940s, it took many years to understand the disease. The awe-inspiring breakthroughs in both science and technology facilitated the recognition of the unique inheritance pattern and the genetic mechanism of fragile X. In this chapter we describe the history and evolution of our understanding of FXS as mirrored by advances in genetics.

A Unique Case of Type 3 Von Willebrand Disease

Background: Von Willebrand disease (vWD) is the most common inherited bleeding disorder worldwide. Genetic mutations in the von Willebrand gene may result in either quantitative (Types 1 and 3 vWD) or qualitative defects (Type 2 vWD) of von Willebrand Factor (vWF). Type 3 is the rarest and most severe form of vWD, resulting in a virtual absence of vWF. Type 3 vWD follows autosomal recessive inheritance and is most often reported in patients who are homozygous for the same gene mutation. We report a patient with type 3 vWD who inherited two different mutations, one from each parent, resulting in compound heterozygosity.Case:Our patient, now a 2 year old female, initially presented with prolonged bleeding lasting approximately 5 hours at the injection site of her 2 month immunizations. Labs on initial presentation showed a normal WBC count, hemoglobin, hematocrit, and platelet count, with normal levels of Factor IX, XI, and XII activity. PTT was prolonged at 59 (reference range 23.3-35.7) with a normal INR. Von Willebrand panel showed markedly decreased Factor VIII (2%), vWF antigen (6%), and vWF activity (8%). VWF multimers were absent, consistent with a diagnosis of type 3 vWD. VWF gene sequence analysis showed two pathologic variants, one on each allele: c2345delC in exon 18 and a deletion within exon 6. Her parents, both 27 years old and with no history of abnormal bleeding, are non-consanguineous. Analysis of parents for vWD revealed that mother is heterozygous for the c2345delC variant and the patient's father is heterozygous for the deletion within exon 6 of the VWF gene. The patient's older sibling who is now 4 years old developed unusual petechiae and bruising after an altercation at school, his testing was positive for only the maternal mutation, resulting in a diagnosis of Type 1 vWD, and a younger brother was negative for both mutations. Our patient has subsequently suffered recurrent episodes of bruising, gingival bleeding, and poor tissue healing and currently requires replacement therapy (prophylaxis) with Humate-P three times each week and additionally as needed.Discussion:Type 3 vWD is quite rare, with a prevalence ranging from 0.1-5.3 per million. Our case is especially interesting due to the unique inheritance pattern resulting in our patient's type 3 vWD phenotype. Type 3 vWD cases are often described in patients homozygous for a mutation in the VWF gene, frequently as a result of consanguinity. Our patient inherited a unique variant from each parent, resulting in heterozygous expression of two defective VWF alleles (compound heterozygosity). Our patient's maternally inherited defect c2435delC in exon 18 is the variant found in the original vWD family described by Dr. Erik von Willebrand in 1926. Less is understood about the paternally inherited defect of a deletion in exon 6 of VWF.In our patient's family, because each parent is heterozygous for a mutation in the VWF gene, future children have a 75% chance of inheriting at least one mutation, and a 25% chance of inheriting both mutations, leading to Type 3 vWD. Type 3 vWD patients have impaired endogenous synthesis of functional vWF, thus therapies such as desmopressin, used in other types of vWD to stimulate secretion of endogenous vWF, are ineffective. Instead, first-line treatment in Type 3 is replacement therapy with Humate-P as needed during bleeding episodes and/or as prophylaxis. Humate P is VWF/FVIII concentrate obtained from pooled human plasma from many carefully screened plasma donors and contains the clotting proteins VWF and FVIII. Humate-P has a VWF:FVIII ratio of approximately 2.4:1. Complications of therapy include the rare development of anti-vWF alloantibodies, which most often occurs in patients with partial or complete VWF gene deletions. Our patient has received aminocaproic acid for minimal bleeding episodes and due to her severe intensity of disease and age of increased risk of injuries had received plasma derived vWF/FVIII concentrates for multiple episodes of moderate bleeding. She has not developed antibodies yet, but is at high risk. The rWVF (recombinant von Willebrand factor) offers new perspective in treatment of vWD more so with type 3 disease. It is a homogenous protein synthesized by a genetically engineered Chinese hamster ovary (CHO) cell line, retains its intact multimer pattern because it is never exposed to proteases(ADAMTS13) which can degrade it. The rVWF is currently in phase 3 clinical trials DisclosuresNo relevant conflicts of interest to declare.

Investigation of 12 X-STR loci in Mongolian and Eastern Han populations of China with comparison to other populations

Due to the unique inheritance pattern, X-chromosomal short tandem repeats (X-STRs) have several advantages in complex kinship cases, such as deficiency cases or grandparent-grandchild and half-sisters testing. In our study, 541 unrelated individuals gathered from Mongolian and Eastern Chinese Han populations were successfully genotyped using the Investigator Argus X-12 kit. We calculated allele/haplotype frequencies and other forensic parameters of the two populations and further explored their genetic distance with already published Chinese populations and six global populations. Our results showed that the 12 X-STR markers were highly informative in the two populations when compared with nine other Chinese populations: significant differences were found at several loci. Geographically neighboring populations or different ethnic groups within the same area appeared to have closer evolutionary relationships. We also analyzed population genetic structure by performing clustering with the STRUCTURE program and Principal Coordinate Analysis (PCoA), and we found that the Chinese and other populations enrolled in this study could be distinguished. Furthermore, Mongolian males were distinguishable from the other studied males by a moderate genetic distance. Our study also expanded the X-STR database, which could facilitate the appropriate application of the 12 X-STR markers in the forensic field in China.

Extreme selective sweeps independently targeted the X chromosomes of the great apes

The unique inheritance pattern of the X chromosome exposes it to natural selection in a way that is different from that of the autosomes, potentially resulting in accelerated evolution. We perform a comparative analysis of X chromosome polymorphism in 10 great ape species, including humans. In most species, we identify striking megabase-wide regions, where nucleotide diversity is less than 20% of the chromosomal average. Such regions are found exclusively on the X chromosome. The regions overlap partially among species, suggesting that the underlying targets are partly shared among species. The regions have higher proportions of singleton SNPs, higher levels of population differentiation, and a higher nonsynonymous-to-synonymous substitution ratio than the rest of the X chromosome. We show that the extent to which diversity is reduced is incompatible with direct selection or the action of background selection and soft selective sweeps alone, and therefore, we suggest that very strong selective sweeps have independently targeted these specific regions in several species. The only genomic feature that we can identify as strongly associated with loss of diversity is the location of testis-expressed ampliconic genes, which also have reduced diversity around them. We hypothesize that these genes may be responsible for selective sweeps in the form of meiotic drive caused by an intragenomic conflict in male meiosis.

XWAS: A Software Toolset for Genetic Data Analysis and Association Studies of the X Chromosome.

XWAS is a new software suite for the analysis of the X chromosome in association studies and similar genetic studies. The X chromosome plays an important role in human disease and traits of many species, especially those with sexually dimorphic characteristics. Special attention needs to be given to its analysis due to the unique inheritance pattern, which leads to analytical complications that have resulted in the majority of genome-wide association studies (GWAS) either not considering X or mishandling it with toolsets that had been designed for non-sex chromosomes. We hence developed XWAS to fill the need for tools that are specially designed for analysis of X. Following extensive, stringent, and X-specific quality control, XWAS offers an array of statistical tests of association, including: 1) the standard test between a SNP (single nucleotide polymorphism) and disease risk, including after first stratifying individuals by sex, 2) a test for a differential effect of a SNP on disease between males and females, 3) motivated by X-inactivation, a test for higher variance of a trait in heterozygous females as compared with homozygous females, and 4) for all tests, a version that allows for combining evidence from all SNPs across a gene. We applied the toolset analysis pipeline to 16 GWAS datasets of immune-related disorders and 7 risk factors of coronary artery disease, and discovered several new X-linked genetic associations. XWAS will provide the tools and incentive for others to incorporate the X chromosome into GWAS and similar studies in any species with an XX/XY system, hence enabling discoveries of novel loci implicated in many diseases and in their sexual dimorphism.

X-Linked Hearing Loss: Two Gene Mutation Examples Provide Generalizable Implications for Clinical Care

To describe the inheritance patterns and auditory phenotype features of 3 Canadian families with mutations in 2 X-linked "deafness" genes (DFNX). Audiological, medical, and family histories were collected and family members interviewed to compare hearing thresholds and case histories between cases with mutations in SMPX versus POU3F4. The family pedigrees reveal characteristic X-linked inheritance patterns. Phenotypic features associated with the SMPX (DFNX4) mutation include early onset in males with rapid progression from mild and flat to sloping sensorineural loss, with highly variable onset and hearing loss severity in females. In contrast, phenotypic features associated with the POU3F4 (DFNX2) mutation are characterized by an early onset, mixed hearing loss with fluctuation in males, and a normal hearing phenotype reported for females. The study shows how this unique inheritance pattern and both gender and mutation-specific phenotype variations can alert audiologists to the presence of X-linked genetic etiologies in their clinical practice. By incorporating this knowledge into clinical decision making, audiologists can facilitate the early identification of X-linked hearing loss and contribute to the effective team management of affected families.

Heteroplasmy in a deep-sea protobranch bivalve suggests an ancient origin of doubly uniparental inheritance of mitochondria in Bivalvia

Most metazoan species have strict maternal inheritance of the mitochondrial genome. In bivalves, a unique inheritance pattern called doubly uniparental inheritance (DUI) occurs in at least seven bivalve families. In this system of mitochondrial inheritance, males inherit and carry mtDNA from both parents, while females only carry mtDNA from the mother. Here, we present evidence of mitochondrial heteroplasmy in deep-sea protobranch bivalves. Divergent 16S rRNA and cytochrome b sequences were obtained within individuals of Ledella ultima. Ledella sublevis also exhibited divergent 16S sequences. Levels of divergence between 16S sequences within individuals were 27 and 15 % for each species, respectively. Ratios of homoplasmic to heteroplasmic individuals were not significantly different from 1:1, in agreement with sex ratios in protobranchs. The results provide the first evidence for mitochondrial heteroplasmy in the protobranchs and suggest DUI might have evolved much earlier in the evolution of the Bivalvia than previously thought.

The use of common mitochondrial variants to detect and characterise population structure in the Australian population: implications for genome-wide association studies

There is an increasing recognition of the potential role of variants in mitochondrial DNA and nuclear-encoded mitochondrial proteins in modifying disease risk. This has led to a rise in the number of mitochondrial association studies being undertaken. The unique inheritance pattern of mitochondria makes mitochondrial DNA variation susceptible to having geographical structure. Such a structure may have a dramatic impact on mitochondrial association studies, particularly in heterogeneous populations. By combining self-reported ancestry data and mitochondrial genotype data for a sample of 3839 individuals from 1037 Australian families, population substructure is tested by looking for evidence of differences in mitochondrial haplogroup and single nucleotide polymorphism (SNP) frequencies between different ancestral groups in Australia. In addition, the substructure within ancestral groups is tested by comparing the similarity of mates to randomly drawn pairs of individuals from the same ancestral group. It is shown that there are significant differences in the frequency of variants both between European and non-European groups, and within Europe. This agrees with previous studies of European mitochondrial variation. No evidence was found for structure within ancestral groups. These results have implications for future association studies in the Australian population, and other populations of heterogeneous ancestry.

Epilepsy and mental retardation limited to females: an under-recognized disorder

Epilepsy and Mental Retardation limited to Females (EFMR) which links to Xq22 has been reported in only one family. We aimed to determine if there was a distinctive phenotype that would enhance recognition of this disorder. We ascertained four unrelated families (two Australian, two Israeli) where seizures in females were transmitted through carrier males. Detailed clinical assessment was performed on 58 individuals, using a validated seizure questionnaire, neurological examination and review of EEG and imaging studies. Gene localization was examined using Xq22 microsatellite markers. Twenty-seven affected females had a mean seizure onset of 14 months (range 6-36) typically presenting with convulsions. All had convulsive attacks at some stage, associated with fever in 17 out of 27 (63%). Multiple seizure types occurred including tonic-clonic (26), tonic (4), partial (11), absence (5), atonic (3) and myoclonic (4). Seizures ceased at mean 12 years. Developmental progress varied from normal (7), to always delayed (4) to normal followed by regression (12). Intellect ranged from normal to severe intellectual disability (ID), with 67% of females having ID or being of borderline intellect. Autistic (6), obsessive (9) and aggressive (7) features were prominent. EEGs showed generalized and focal epileptiform abnormalities. Five obligate male carriers had obsessional tendencies. Linkage to Xq22 was confirmed (maximum lod 3.5 at = 0). We conclude that EFMR is a distinctive, under-recognized familial syndrome where girls present with convulsions in infancy, often associated with intellectual impairment and autistic features. The unique inheritance pattern with transmission by males is perplexing. Clinical recognition is straightforward in multiplex families due to the unique inheritance pattern; however, this disorder should be considered in smaller families where females alone have seizures beginning in infancy, particularly in the setting of developmental delay. In single cases, diagnosis will depend on identification of the molecular basis.

THE X-FILES OF INFLAMMATION

Females as compared with males display better general health status, longevity, and improved clinical course after injury and infection. It is generally believed that the female advantage is associated with the effects of sex hormones. This review argues that the sex benefit of females during the host response is associated with polymorphism of X-linked genes and cellular mosaicism for X-linked parental alleles. Cells from females carry both parental X chromosomes (maternal, Xm; or paternal, Xp), whereas males carry only one (Xm). Because of dosage compensation and random X inactivation, half of the cells from females express either Xm or Xp. Therefore, females are cellular mosaics for their X-linked polymorphic genes. This cellular mosaicism in females represents a more adaptive and balanced cellular machinery that is advantageous during the innate immune response. Several genes encoding key metabolic and regulatory proteins reside on the X chromosome, including members of the apoptotic cascade, hormone homeostasis, glucose metabolic enzymes, superoxide-producing machinery, and the toll-like receptor/nuclear factor kappaB/c-Jun N-terminal kinase signaling pathway. Polymorphic forms of these X-linked proteins are likely to manifest in phenotypic differences in the mosaic cell populations in females and may contribute to sex-related differences in the host response to injury and infection. The unique inheritance pattern of X-linked polymorphisms and their potential confounding effects in clinical trials are also discussed; furthermore, we present potential biomarkers for studying mosaic cell populations of innate immunity.

Submicroscopic deletion in cousins with Prader-Willi syndrome causes a grandmatrilineal inheritance pattern: Effects of imprinting

The Prader-Willi syndrome (PWS) critical region on 15q11-q13 is subject to imprinting. PWS becomes apparent when genes on the paternally inherited chromosome are not expressed. Familial PWS is rare. We report on a family in which a male and a female paternal first cousin both have PWS with cytogenetically normal karyotypes. Fluorescence in situ hybridization (FISH) analysis shows a submicroscopic deletion of SNRPN, but not the closely associated loci D15S10, D15S11, D15S63, and GABRB3. The cousins' fathers and two paternal aunts have the same deletion and are clinically normal. The grandmother of the cousins is deceased and not available for study, and their grandfather is not deleted for SNRPN. DNA methylation analysis of D15S63 is consistent with an abnormality of the imprinting center associated with PWS. "Grandmatrilineal" inheritance occurs when a woman with deletion of an imprinted, paternally expressed gene is at risk of having affected grandchildren through her sons. In this case, PWS does not become evident as long as the deletion is passed through the matrilineal line. This represents a unique inheritance pattern due to imprinting.

Fragile X Syndrome

Fragile X syndrome is a recently identified genetic disorder considered to be the most common inherited form of mental retardation. Current research is revealing that this chromosomal anomaly is linked to a variety of other educationally relevant problems including learning disabilities, attention deficit disorders, speech and language deficits, autistic characteristics, and behavior disorders. A description of the unique inheritance pattern reveals why milder forms of the syndrome are now beginning to be identified and educational interventions applied. This review highlights the physical, intellectual, academic, behavioral, and communication characteristics associated with fragile X. With knowledge of fragile X syndrome, the educator can play a key role in recognizing the disorder and referring for both early diagnosis and genetic counseling.