Nonrandom Transmission Research Articles

Inheritance of plumage morphs in Little Eagles Hieraaetus morphnoides in northern New South Wales

Polymorphism and inheritance of plumage colour in the Little Eagle Hieraaetus morphnoides were studied in northern New South Wales, by tallying records of parental morph combinations in breeding pairs and the morphs of their offspring in the 1980s, 2000s and 2017–2019 ( n = 41 pair combinations). The average ratio in breeding adults was 4.9 light:1 dark, with dark males outnumbering dark females (1.8:1). Light × light pairs always produced light young ( n = 32). Dark male × light female pairs variously produced light and dark offspring of both sexes ( n = 12). Light male × dark female pairs produced dark young of either sex ( n = 4) and one light young of unknown sex. One dark × dark pair produced a dark young. We conclude a Mendelian inheritance pattern with the dark morph recessive. From a small sample of mixed pairs with a dark male, the ratio of offspring morphs did not differ significantly from that expected by the Hardy–Weinberg equation, but mixed pairs with a light male produced 4 dark offspring to one light, versus the expected Hard –Weinberg ratio of 1.95 light: 1 dark. This outcome suggests a non-random transmission of the dark allele by heterozygous light males, and a similar pattern of inheritance to that in the related Booted Eagle H. pennatus .

Population genetic structure of the parasitic nematode Spirocerca lupi in South Africa

Spirocerca lupi is a parasitic nematode of canids and occurs in most tropical and subtropical regions around the world. While its life cycle is well known, insight is lacking about its mating structure within-hosts, genetic variability and long-distance dispersal ability. These characteristics contribute significantly to the dynamics and spread of potential resistance genes, which impacts on the control of S. lupi. To evaluate the population structure and infer potential mating behaviour of S. lupi, we genotyped 130 samples at nine microsatellite loci from three geographical locations in South Africa, between 600 and 1000 km apart. These loci identified unique individuals with high levels of polymorphism suggesting that these are not newly established S. lupi populations in South Africa and that effective population sizes must be large. Population genetic analyses showed that populations are not very distinct, that worms within dogs are more similar to each other than random worms from each population, and that mating is at random within dogs. We can thus infer that the parasite is frequently transported over great distances. Even so, two genetically distinct populations could be identified. Relatedness of worms within dogs were significantly higher than between dogs and together with F-statistics suggests some non-random transmission of parasites between hosts. While mating is random within a host, parasites from a host are more likely to be related and hence an increase in homozygosity is seen. The implications of this genetic structure on parasite control are considered.

Non-random transmission of parental alleles into crop-wild and crop-weed hybrid lineages separated by a transgene and neutral identifiers in rice

It is essential to assess environmental impact of transgene flow from genetically engineered crops to their wild or weedy relatives before commercialization. Measuring comparative trials of fitness in the transgene-flow-resulted hybrids plays the key role in the assessment, where the segregated isogenic hybrid lineages/subpopulations with or without a transgene of the same genomic background are involved. Here, we report substantial genomic differentiation between transgene-present and -absent lineages (F2-F3) divided by a glyphosate-resistance transgene from a crop-wild/weed hybrid population in rice. We further confirmed that such differentiation is attributed to increased frequencies of crop-parent alleles in transgenic hybrid lineages at multiple loci across the genome, as estimated by SSR (simple sequence repeat) markers. Such preferential transmission of parental alleles was also found in equally divided crop-wild/weed hybrid lineages with or without a particular neutral SSR identifier. We conclude that selecting either a transgene or neutral marker as an identifier to create hybrid lineages will result in different genomic background of the lineages due to non-random transmission of parental alleles. Non-random allele transmission may misrepresent the outcomes of fitness effects. We therefore propose seeking other means to evaluate fitness effects of transgenes for assessing environmental impact caused by crop-to-wild/weed gene flow.

Characterization of nine microsatellite loci for Dicrocoelium dendriticum, an emerging liver fluke of ungulates in North America, and their use to detect clonemates and random mating

This study characterizes polymorphic microsatellite loci from adults of the liver fluke Dicrocoelium dendriticum sampled from a population of sympatric beef cattle and wapiti in a region of emergence in southern Alberta, Canada. We also scrutinized the markers to validate their use in studying the population genetics of this complex life cycle parasite. Among the nine loci described, four deviated significantly from Hardy Weinberg Equilibrium (HWE) due to technical artefacts. The remaining five loci were in HWE. These five provided sufficient resolution to identify clonemates produced from the obligate asexual reproduction phase of the life cycle in snails and to assess the impact of non-random transmission of clonemates on measures of FIS, FST and genotypic disequilibrium. Excluding clonemates, we show that the sub-population of worms was in HWE, that average FIS within hosts was 0.003 (p=0.4922) and that there was no population genetic structure among hosts FST=0.001 (p=0.3243). These markers will be useful for studies of Dicrocoelium dendriticum ecology, transmission, and evolution.

Testing local-scale panmixia provides insights into the cryptic ecology, evolution, and epidemiology of metazoan animal parasites

When every individual has an equal chance of mating with other individuals, the population is classified as panmictic. Amongst metazoan parasites of animals, local-scale panmixia can be disrupted due to not only non-random mating, but also non-random transmission among individual hosts of a single host population or non-random transmission among sympatric host species. Population genetics theory and analyses can be used to test the null hypothesis of panmixia and thus, allow one to draw inferences about parasite population dynamics that are difficult to observe directly. We provide an outline that addresses 3 tiered questions when testing parasite panmixia on local scales: is there greater than 1 parasite population/species, is there genetic subdivision amongst infrapopulations within a host population, and is there asexual reproduction or a non-random mating system? In this review, we highlight the evolutionary significance of non-panmixia on local scales and the genetic patterns that have been used to identify the different factors that may cause or explain deviations from panmixia on a local scale. We also discuss how tests of local-scale panmixia can provide a means to infer parasite population dynamics and epidemiology of medically relevant parasites.

Preferential transmission of genetic risk variants of candidate loci at 6p21 from asymptomatic grandparents to mothers of children with neonatal lupus

Neonatal lupus (NL) occurs in fetuses exposed to maternal anti-SSA/Ro and/or anti-SSB/La antibodies, although the mothers themselves may not manifest any clinical disease. A focus on transmission of risk factors for NL from maternal grandparents to mothers of children with NL may yield dividends toward understanding the aggregation of autoantibodies and genetic factors in affected families. This study was perforned to determine the role of maternal grandparents in the development of the autoimmune phenotype of mothers of children with NL. Fifty-one mothers of children with cardiac and/or cutaneous NL, 48 maternal grandmothers, and 35 maternal grandfathers in the Research Registry for Neonatal Lupus were interrogated for clinical symptoms by questionnaire and underwent laboratory assessments, including determination of anti-SSA/Ro and anti-SSB/La antibody status (by enzyme-linked immunosorbent assay) and genotype at rs1800629 (TNFα) and rs7775397 (C6orf10) (allelic discrimination). The transmission disequilibrium test (TDT) was computed to test for nonrandom transmission from maternal grandparents to mothers of children with NL. The common phenotypic feature in mothers of children with NL was the autoantibody and not the clinical profile; 7 had lupus, 14 had Sjögren's syndrome, 7 had both, and 23 were asymptomatic. Mothers of children with NL were significantly enriched for the risk alleles at both TNFα and C6orf10. The grandparents of children with NL carried minimal burden for autoimmune disease or abnormal antibody production and were not enriched in the genetic risk factors. However, the TDT analysis showed significant excess transmission of the risk alleles at both TNFα (odds ratio [OR] 6.67, P = 3.93 × 10(-4) ) and C6orf10 (OR 35.0, P = 3.74 × 10(-5) ) to mothers of children with NL. Mothers of children with NL are enriched for the TNFα and C6orf10 risk alleles, which are preferentially inherited from the asymptomatic maternal grandparents. These findings support the hypothesis that the development of NL and genetic etiology are multigenerational.

More than meets the eye: detecting cryptic microgeographic population structure in a parasite with a complex life cycle

Nonrandom recruitment of parasites among hosts can lead to genetic differentiation among hosts and mating dynamics that promote inbreeding. It has been hypothesized that strictly aquatic parasites with intermediate hosts will behave as panmictic populations among hosts because ample opportunity exists for random mixing of unrelated individuals during transmission to the definitive host. A previous allozyme study on the marine trematode Lecithochirium fusiforme did not support this hypothesis; in that, there was genetic differentiation among, and significant heterozygote deficiencies within, definitive hosts. We revisit this system and use microsatellites to obtain multilocus genotypes. Our goal was to determine whether cryptic subgroups and/or the presence of clones could account for the apparent deviation from 'panmixia'. We find strong evidence for cryptic subdivision (three genetic clusters) that causes the Wahlund effect and differentiation among definitive hosts. After accounting for these cryptic groups, we see panmictic genetic structure among definitive hosts that is consistent with the 'high mixing in aquatic habitats' hypothesis. We see evidence for cotransmission of clones in all three clusters, but this level of clonal structure did not have a major impact in causing deviations from Hardy-Weinberg equilibrium, and only affected genetic differentiation among hosts in one cluster. A cursory examination of the data may have led to incorrect conclusions about nonrandom transmission. However, it is obvious in this system that there is more than meets the eye in relation to the actual make-up of parasite populations. In general, the methods we employ will be useful for elucidating hidden patterns in other organisms where cryptic structure may be common (e.g. those with limited morphology or complex life histories).

A robust TDT‐type association test under informative parental missingness

Many family-based association tests rely on the random transmission of alleles from parents to offspring. Among them, the transmission/disequilibrium test (TDT) may be considered to be the most popular statistical test. The TDT statistic and its variations were proposed to evaluate nonrandom transmission of alleles from parents to the diseased children. However, in family studies, parental genotypes may be missing due to parental death, loss, divorce, or other reasons. Under some missingness conditions, nonrandom transmission of alleles may still occur even when the gene and disease are not associated. As a consequence, the usual TDT-type tests would produce excessive false positive conclusions in association studies. In this paper, we propose a novel TDT-type association test which is not only simple in computation but also robust to the joint effect of population stratification and informative parental missingness. Our test is model-free and allows for different mechanisms of parental missingness across subpopulations. We use a simulation study to compare the performance of the new test with TDT and point out the advantage of the new method.

Genetic contribution of chemokine receptor 2 (CCR2) polymorphisms towards increased serum total IgE levels in Indian asthmatics

The chemokine (C–C motif) receptors (CCR) 2 and 5 are members of a large family of G protein-coupled receptors, playing important roles in asthma pathogenesis. Using standard sequencing techniques, a total of 15 single nucleotide and 8 insertion/deletion polymorphisms (DIPs) (5 novels) were identified in and around these two genes. None of the studied polymorphisms ( N = 7, selected on the basis on linkage disequilibrium) was associated with asthma in a case ( N = 315) – control ( N = 337) study and showed no evidence for non-random transmission to individuals with asthma/atopy in Indian pedigrees ( n = 235). However, multilocus haplotype analysis based on simulations yielded a P = 0.00005 in the case–control study and a P = 0.03 for the family-based association studies. Furthermore, rs3918356 and rs743660 polymorphisms in CCR2 were found to be associated with total serum IgE levels in both the study designs. Thus, our study supports a significant role for chemokine receptor polymorphisms in genetic susceptibility to asthma.

CFTR mutations and reproductive outcomes in a population isolate

Multiple hypotheses have been proposed to explain the high incidence of cystic fibrosis in Caucasian populations. Most rely on a fitness advantage to carriers of CF mutations, either through increased resistance to infectious disease, such as cholera, or through increased fertility. In this study we tested the latter hypothesis in the Hutterites of South Dakota, a genetic isolate with a relatively high CF carrier frequency. Following a population-wide screen for the only two mutations present in the Hutterites (M1101K, DeltaF508), we tested for associations between carrier status and measures of fertility. There was no evidence of nonrandom transmission of mutations (P = 0.409) or skewed sex ratios (P = 0.847) in children of carrier parents. Moreover, carrier status was not associated with overall fertility (P = 0.597 for carrier fathers and 0.694 for carrier mothers). Although carrier males' sibship sizes were larger than carrier females' sibship sizes (P = 0.049), this was not significant after accounting for multiple testing. Overall, our results suggest that if there is a fertility advantage among CF carriers, it is too small to be detected in our sample (85 carriers out of approximately 950 screened), or the effects are confined to DeltaF508 carriers, for which there are too few in our sample to test this specific hypothesis.

Transmission ratio distortion in the human body louse, Pediculus humanus (Insecta: Phthiraptera)

We studied inheritance at three microsatellite loci in eight F, and two F2 families of the body (clothes) louse of humans, Pediculus humanus. The alleles of heterozygous female-parents were always inherited in a Mendelian fashion in these families. Alleles from heterozygous male-parents, however, were inherited in two different ways: (i) in a Mendelian fashion and (ii) in a non-Mendelian fashion, where males passed to their offspring only one of their two alleles, that is, 100% nonrandom transmission. In male body lice, where there was non-Mendelian inheritance, the paternally inherited set of alleles was eliminated. We interpret this pattern of inheritance as evidence for extreme transmission ratio distortion of paternal alleles in this species.

A novel meiotic drive locus almost completely distorts segregation in mimulus (monkeyflower) hybrids.

We report the discovery, mapping, and characterization of a meiotic drive locus (D) exhibiting nearly 100% nonrandom transmission in hybrids between two species of yellow monkeyflowers, outcrossing Mimulus guttatus and selfing M. nasutus. Only 1% of F(2) hybrids were M. nasutus homozygotes at the marker most tightly linked to D. We used a set of reciprocal backcrosses to distinguish among male-specific, female-specific, and zygote-specific sources of transmission ratio distortion. Transmission was severely distorted only when the heterozygous F(1) acted as the female parent in crosses to either parental species, ruling out pollen competition and zygote mortality as potential sources of drive. After four generations of backcrossing to M. nasutus, nearly isogenic lines were still >90% heterozygous at markers linked to D, suggesting that heterozygosity at the drive locus alone is sufficient for nonrandom transmission. A lack of dramatic female fitness costs in these lines rules out alternatives involving ovule or seed mortality and points to a truly meiotic mechanism of drive. The strength and direction of drive in this system is consistent with population genetic theory of selfish element evolution under different mating systems. These results are the first empirical demonstration of the strong female-specific drive predicted by new models of selfish centromere turnover.

Mutant BRCA1 alleles transmission: different approaches and different biases.

Recently, a non-random transmission of BRCA1 mutant alleles to the off-spring of carriers has been suggested. If confirmed by further studies, the finding will have important implications both for risk assessment and the understanding of BRCA1 biology. However, these kind of analysis are not easy to perform due to several ascertainment biases inherent to the identification of BRCA1 carriers. In this report we propose different approaches to overcome such biases and we present additional data supporting a non-random transmission of BRCA1 mutant alleles.

Non-random transmission of mutant alleles to female offspring of BRCA1 carriers in Poland

Constitutional mutations in the BRCA1 gene predispose to an autosomal dominant syndrome of breast and ovarian cancer. The lifetime penetrance of BRCA1 gene mutations is high; approximately 50% of women with mutations will be affected by cancer by the age of 50 years, and over 80% of women with mutations will be affected with cancer by the age of 75 years.1 At birth, it is expected that 50% of the children of a carrier parent will inherit a mutant allele. If the mortality in carriers is higher in carriers than in non-carriers, then the proportion of carriers among offspring is expected to decline with age. Similarly, among unaffected women, the proportion of carriers is expected to decline with age. For example, if the gene is 50% penetrant by by the age of 50 years, then one third of a sample of healthy 50 year old female offspring of carriers are expected to be carriers. Under the assumption that a mutant allele is transmitted to 50% of offspring, it is therefore possible to estimate age-specific penetrance values of the BRCA1 gene by counting the relative number of carriers and non-carriers in a sample of healthy offspring, of varying ages, of carrier parents. Three founder mutations in BRCA1 are common in Poland (5382insC, C61G, and 4153delA).2 In an attempt to estimate the age-specific penetrance of these three mutations, we systematically reviewed the genotypes of mothers and daughters in a selected group of …

A trisomic transmission disequilibrium test.

Certain congenital disorders that are rare in the general population are quite common in individuals with trisomic conditions. For example, complete atrioventricular septal defect occurs in about 20% of individuals with Down syndrome, an approximately 500-fold increase in risk as compared to individuals without Down syndrome. Genetic variation on the chromosome involved in the trisomy may affect susceptibility to these trisomy-specific disorders. That is, increased dosage of a variant may be directly involved in increasing the risk of a disorder, or it may be indirectly involved by causing up- or downregulation of other genes. As in standard disomic gene-mapping, one can search for genes using linkage or association methods. Within association methods, one can consider case-control methods or family-based control methods such as the transmission disequilibrium test (TDT). Most gene-mapping methods need to be substantially redesigned for use with trisomic data. In this paper, we present a "trisomic TDT", a statistical method of testing for nonrandom transmission of alleles from parents to trisomic children. We demonstrate the method on a dataset of parent-child trios in which the child has Down syndrome.

Genetic association studies: What are they teaching clinicians?

Genetic association studies: What are they teaching clinicians?

Sequence variation in the promoter region of the cholinergic receptor muscarinic 3 gene and asthma and atopy

Background: Muscarinic acetylcholine receptors are members of the superfamily of G protein–coupled, 7 transmembrane– spanning proteins. They are important in the development of airway hyperresponsiveness. In the lung the M3 receptor, encoded by the cholinergic receptor muscarinic 3 gene, is present in airway smooth muscle and mediates smooth muscle contraction. Objective: We considered the cholinergic receptor muscarinic 3 gene as a possible candidate gene for bronchial asthma and initiated studies to identify polymorphisms in the promoter region. Method: We identified 4 single-nucleotide polymorphisms (−708A/G, −627G/C, −513C/A, and −492C/T) and 2 short tandem repeat polymorphisms, a tetranucleotide (CTTT)12-20 and a dinucleotide (GT)6-19 repeat. Results: None of the identified single nucleotide polymorphisms were significantly more frequent in asthmatic patients (n = 76) compared with in healthy control subjects (n = 81). Furthermore, there was no evidence for nonrandom transmission of short tandem repeat polymorphism haplotypes to individuals with asthma or bronchial hyperresponsiveness (P > .50) in a large Hutterite pedigree. However, there was significant nonrandom transmission of haplotypes to individuals with skin test reactivity to cockroach allergens (global transmission disequilibrium test: χ2 = 38.55, P = .013). Conclusions: These results suggest a possible role for this gene in atopic disorders. (J Allergy Clin Immunol 2003;111:527-32.)

Support for allelic association of a polymorphic site in the promoter region of the serotonin transporter gene with risk for alcohol dependence.

An association between the 5-HTTLPR short variant polymorphism in the promoter region of the serotonin transporter gene and risk for alcohol dependence has been reported from case-control studies that are, however, prone to chance findings related to artifacts of population structure. The authors sought additional evidence for this association from a family-based study. Ninety-two alcohol-dependent probands and their parents were tested for nonrandom transmission of alleles from heterozygous parents to affected probands. Preferential transmission of the short allele was found (65 of 102 transmissions from heterozygous parents). The results suggest allelic association between a variant in the promoter region of the serotonin transporter gene and the risk for alcohol dependence. However, it remains to be seen whether the functional properties of this variant are directly responsible for the increased risk to alcohol dependence.

Organelle DNA and male fertility variation in Solanum spp. and interspecific somatic hybrids

Novel and potentially useful genetic variation in cytoplasmic genomes can be induced by interspecific somatic hybridization in plants. To evaluate such variability and correlate it with nuclear-cytoplasmic interactions leading to male sterility in Solanum spp., we examined progeny of male-sterile and male-fertile somatic hybrids between Solanum tuberosum (tbr), the common potato, and S. commersonii (cmm), a wild species showing sexual incongruity with tbr, for fertility and organelle DNA composition. Uniform male-fertile and male-sterile progenies were obtained by selfing the male-fertile hybrid and crossing the male-sterile ones, indicating maternal inheritance of the fertility phenotype. The two fusion partners were only slightly differentiated in the plastidial genome. MtDNA polymorphism between the species was greater, although its extent varied with the genomic region investigated. All somatic hybrids had non-parental organelle genomes, with reassorted organelles and/or rearranged mitochondria (i.e., cmm-specific bands for some regions and tbr-specific bands for others). Mitochondria reassorted independently from chloroplasts. Most hybrids showed the cmm cpDNA hybridization pattern, indicating non-random transmission of chloroplasts. Most male-sterile hybrids showed preferential inheritance of tbr mtDNA fragments. The male-fertile somatic hybrid clone had predominantly cmm mtDNA fragments. This result suggests that a tbr-derived region involved in nuclear-cytoplasmic incompatibility and male sterility has been lost by rearrangement; however, no clear correlation between a specific mitochondrial region and male sterility has been found so far.

Analysis of HLA haplotype segregation in the Schmiedeleut Hutterites of South Dakota.

HLA data from 1,085 South Dakotan Schmiedeleut Hutterites were examined for evidence of nonrandom transmission of haplotypes. The inheritance of haplotypes was viewed as a series of genetic contests between competing pairs of parental haplotypes using a maximum likelihood approach first put forward by Carlisle and Woodbury. Haplotype transmission probabilities were expressed in terms of weights, and the null hypothesis that the inheritance pattern was a random stochastic process, equivalent to the equality of the weights, was tested via the likelihood ratio. A total of 1,517 competitions was subjected to analysis, first globally using all data, and then for particular haplotypes of interest. Transmission of haplotype observed to compete with only a single other haplotype was also assessed using an exact procedure. No evidence of preferential transmission of HLA haplotypes was found. These results do not rule out transmission biases that may arise because of selection against homozygotes, mechanisms specifically affecting particular alleles or haplotypes not considered in the present study, or biases arising from maternal-fetal interactions.