Rules Of Mendelian Inheritance Research Articles

О ПЕРВИЧНОЙ ГЕНЕТИЧЕСКОЙ ДИВЕРГЕНЦИИ В СИСТЕМЕ ПОПУЛЯЦИЙ НА КОЛЬЦЕВОМ АРЕАЛЕ

The article proposes and studies a discrete time model of the number dynamics and genotype frequencies in a one-dimensional ring of populations coupled by migration. We consider panmictic populations with Mendelian rules of inheritance and monolocus selection directed against heterozygotes. The model has two layers of connected maps (ensembles). The first layer describes the number dynamics in each local site, including migration from adjacent sites. The growth rates of each subpopulation depend on the genotype frequencies, which change during evolution towards one of the limiting genetic structures. The second level describes the dynamics of genotype frequencies, considering the fact that gene influx depends on the ratio of population abundance. Here, the more numerous is the population giving the migrant flow (or less numerous is the receiving population), the stronger is the gene flow. We have considered two variants of migration: constant (deterministic), in which the fraction of migrants is fixed, and random, in which the number of emigrants from the local population is chosen randomly (random drift) and is not constant. The model studies the conditions and mechanisms of differentiation by genotypes between different parts of a homogeneous range (divergence). It has been shown that with reduced fitness of heterozygotes, spatial-temporal dynamics are characterized by stripes where homozygotes predominate. Between the stripes with opposite forms (alleles), there locate the stripes with heterozygotes, their existence supporting due to migrations from opposite sites. With deterministic migration, this pattern exists for a short time and most often appears as vertical stripes. With random drift, the stripes take the form of traveling waves, which persist for a long time under certain limitations on population growth. The authors show that significant differences inevitably arising in the number and dynamics patterns in different parts of the area, are caused by divergence.

Effect of uniparental disomy in parentage testing

Uniparental disomy (UPD) is a rare type of chromosomal aberration that may hinder the analysis of kinship during forensic identification. Here, we investigated these genetic findings to avoid false exclusions during parentage testing. Thirty-nine fluorescently labeled, autosomal short tandem repeats (STR) were amplified in three cases, to detect parent–child relationships. Twenty-three fluorescently labeled Y-chromosome STRs were also employed. These were subjected to capillary electrophoresis. The parentage index was calculated by the bipartite or tripartite model. Single nucleotide polymorphism (SNP) microarrays were performed to further investigate the genetic mechanisms. The conclusions supported the biological mother–child relationship in three cases. However, in all cases, the alleged father and child had three autosomal STR markers, constrained to a single chromosome, which did not conform to Mendelian inheritance rules. The genotyping of 23 Y-chromosome STRs did not reveal any violations of Mendelian law. The combination of STR profiling and SNP microarrays suggested that two children had maternal UPD of chromosome 7, whilst one had UPD of chromosome 2. After excluding the three incompatible loci, the conclusions supported the biological father-child relationship in all cases. The same results were obtained when parentage testing of trios was used. Uniparental disomy may complicate the judgment of kinship in parentage testing. The possibility of UPD should be considered when incompatible STR loci are found on the same chromosome. Genetic evidence obtained through additional molecular techniques can provide better interpretation of kinship in the presence of UPD and avoid false exclusions of biological relationships.

The Evolutionary Dynamics of a Sex-Structured Population with Non-Overlapping Generations

This paper proposes and studies a discrete-time model for a sex-structured population with non-overlapping generations under density-dependent regulation of survival. The population is assumed to have genetic variety among individuals in terms of reproductive potential, controlled by a single autosomal diallelic locus. We consider a panmictic population with Mendelian inheritance rules. We examine the stability model and show that increasing the average value of reproductive potential destabilizes the population dynamics. The scenario of stability loss in fixed points via period doubling or Neimark–Sacker bifurcations depends on the intensity of the self-regulation. The growth rate at which the population survives and develops is shown to depend on the fitness of the genotypes and the secondary sex ratio. As a result, the asymptotic genetic composition of the population is determined by the values of the reproductive potentials of the heterozygote and homozygotes, the initial conditions, and the parameter describing the ratio of newborn females to males. With disruptive selection, the influence of external factors changing the current genetic composition of a population can alter the direction of evolution and lead to the extinction of a successful developing population or a gradual population recovery due to evolutionary rescue after a noticeable decline in its abundance.

Evidential segregation analysis for offspring sex ratio in rabbit and sheep populations

Offspring sex ratio has been found to be altered by environmental and genetic distortions in multiple species, against the Mendelian inheritance rules. However, little is known in livestock populations where it is essential to validate whether a polymorphic major gene with relevant effects may segregate in the target population. However, the current analytical tool (model FREQ) cannot handle new mutations in non-founder individuals, reducing the chance of detecting them. Our new analytical approach aimed to overcome this limitation in the context of evidential inference, a statistical framework based on the likelihood function as a robust objective measure of the strength of statistical evidence without variation from the sample size. Two field data sets from sheep and rabbit populations were used. Models evaluated environmental and inbreeding effects in both species. Our new approach assumed that the mutation primarily arose in an individual of the analyzed data set (model MUTj). Each sire was individually analyzed to determine the most plausible source for the new mutation, if any. The likelihood ratio (LR) against a reference parametrization without mutations (model NULL) was used to test the statistical relevance of systematic effects (LR ≥ 8) and models (LR ≥ 32). Both species revealed relevant departures for offspring sex ratio along the analyzed time frame with strong evidence for the year (LR = 1.4 × 109 in Ripollesa sheep and LR = 85.7 in MARET rabbits) and season (LR = 12.6 in MARET rabbits), although with a fluctuating pattern. The age of the dam reported weak evidence in both species (LR < 4). Inbreeding had a relevant linear impact on both sheep (LR = 60.7) and rabbit (LR = 780.4) populations, whereas the quadratic effect only showed strong evidence in MARET rabbits (LR = 8.3). Regarding the segregation analysis, most models showed an almost homozygous pattern of weak or lacking evidence of new mutations influencing offspring sex ratio. The only species showing strong evidence for the MUTj model (LR > 32) was the Ripollesa sheep, with a ram three to six generations from the founders as the most likely source for a new mutation increasing the odds of daughters. The additive genetic effect of this model for the mutant allele also had strong evidence (LR = 1,195). Therefore, the MUTj parametrization can be a valuable analytical tool to check for the possibility of new mutations along the pedigree files, not only before the founders.

A case study on genomic imprinting facilitates student learning.

Problem-based learning encourages students to deepen their understanding of a concept by working through a real-world example of course content. Case studies represent a form of problem-based learning that engages students in realistic scenarios to achieve a deeper understanding of concepts. Case studies have been shown to facilitate the learning of challenging subject matter. We hypothesized that the use of a case study would help students better learn the topic of genomic imprinting, an abstract phenomenon in molecular biology and genetics. We wrote an interrupted case study that focused on genomic imprinting. The case study consists of three short popular news articles that relate to genomic imprinting. Each article is followed by a set of two to four questions. Students read each article and discuss its associated questions in small groups and then with the entire class before moving on to the next article. We deployed the case study in an intermediate-level molecular biology course at a small, liberal arts university. We assessed student learning and attitudes toward the case study (50 pre/postmatched pairs). In four true/false assessment questions, our results showed that the students' performance on the assessment after the case study was significantly higher than their performance before the case study. Students also self-reported increased knowledge of concepts related to genomic imprinting. Finally, students were likely to agree that the case study was beneficial to their learning and was an enjoyable classroom activity. We conclude that the case study is an effective way to instruct students about the topic of genomic imprinting.NEW & NOTEWORTHY Students often struggle with the concept of genomic imprinting, in part because it violates Mendelian rules of inheritance. Students learned about genomic imprinting, and enjoyed doing it when completing this case study.

Генетическая дивергенция в системе смежных популяций при плотностно-зависимом лимитировании гаметопродукции

The paper studies the mechanisms leading to the emergence of genetic divergence (stable genetic differences) between two populations coupled by migration. We considered the classical system of panmictic populations with Mendelian rules of inheritance and monolocus selection directed against heterozygotes. In order to limit the growth of populations, we propose to assume that gamete production and total fertility (birth) decreases with population growth due to limited resources. We have proposed a non-linear discrete time model that describes the concentration dynamics of one of the alleles and each population abundance. To calculate the coordinates of all fixed points corresponding to different types of the limiting genetic structure and the abundance ratio, we have proposed a method for calculating their coordinates. It is shown that with a density-dependent birth limitation in the model, a set of fixed points corresponding to a homogeneous and heterogeneous distribution is possible. At a homogeneous distribution, both populations are monomorphic, with individuals belonging to only one genotype. At this, the limiting values of population abundance do not always coincide. With a non-homogeneous distribution, adjacent populations are polymorphic with individuals of different genotypes, but they differ significantly in the frequencies of alternative alleles and asymptotic population abundance. Bifurcations of the fixed points birth corresponding to heterogeneous distribution and genetic divergence are described. It is found that the movement towards one of the possible limiting genetic structures is accompanied by a change in the reproductive capabilities of populations.It is shown that a reduced fitness of heterozygotes in monomorphic populations results in a higher birth rate as compared to polymorphic populations obviously containing individuals with different reproductive capabilities. As a result, monomorphic and polymorphic populations correspond to different limiting abundances and cycles with different periods and oscillation phases after the loss of stability, even if the populations are completely identical.

Genotype error biases trio-based estimates of haplotype phase accuracy

Haplotypes can be estimated from unphased genotype data via statistical methods. When parent-offspring trios are available for inferring the true phase from Mendelian inheritance rules, the accuracy of statistical phasing is usually measured by the switch error rate, which is the proportion of pairs of consecutive heterozygotes that are incorrectly phased. We present a method for estimating the genotype error rate from parent-offspring trios and a method for estimating the bias that occurs in the observed switch error rate as a result of genotype error. We apply these methods to 485,301 genotyped UK Biobank samples that include 898 White British trios and to 38,387 sequenced TOPMed samples that include 217 African Caribbean trios and 669 European American trios. We show that genotype error inflates the observed switch error rate and that the relative bias increases with sample size. For the UK Biobank WhiteBritish trios, the observed switch error rate in the trio offspring is 2.4 times larger than the estimated true switch error rate (1.4×10-3 vs 5.8×10-4. We propose an alternate definition of phase error that counts two consecutive switch errors as a single error because back-to-back switch errors arise when a single heterozygote is incorrectly phased with respect to the surrounding heterozygotes. With this definition, we estimate that the average distance between phase errors is 64 megabases in the UK Biobank White British individuals.

Simple and complex dynamics in the model of evolution of two populations coupled by migration with non-overlapping generations

Purpose is to study the mechanisms leading to genetic divergence (stable genetic differences between two adjacent populations). We considered the following classical model situation. Populations are panmictic with Mendelian rules of inheritance. The action of natural selection (differences in fitness) on each of population is the same and is determined by the genotypes of only one diallel locus. We assume that adjacent generations do not overlap and genetic transformations can be described by a discrete time model. This model describes the change in the concentration of one of the alleles in each population and the ratio (weight) of first population to the total size. Methods. We used the analogue of saddle charts to construct parametric portraits showing the domains of qualitatively different dynamic modes. The study is supplemented with phase portraits, basins of attraction and bifurcation diagrams. Results. We found that the model dynamic regimes qualitatively coincide with the regimes of a similar model with continuous time, but only for a weak migration. With a strong coupling, fluctuations of the phase variables are possible. We showed that the genetic divergence is possible only with reduced fitness of heterozygotes and is the result of a series of bifurcations: pitchfork bifurcation, period doubling, or saddle-node bifurcation. After these qualitative changes, the dynamics become bi- or quadstable. In the first case, the solutions corresponding to the genetic divergence are unstable and are just a part of the transient process to monomorphic state. In the second case, the divergence is stable and appears as 2-cycle for a strong migration coupling. Conclusion. In neighboring populations, movement towards an asymptotic genetic structure (monomorphism, polymorphism or divergence) can be strictly monotonous or in the form of damped unstable or undamped stable fluctuations with a period of 2 for biologically significant parameters. For insignificant parameters, we found a complex dynamics (chaos) that consist of divergent fluctuations around fixed points and quasi-random transitions between them.

A Non-Rogue Mutant Line Induced by ENU Mutagenesis in Paramutated Rogue Peas (Pisum sativum L.) Is Still Sensitive to the Rogue Paramutation.

The spontaneously emerging rogue phenotype in peas (Pisum sativum L.), characterized by narrow and pointed leaf stipula and leaflets, was the first identified case of the epigenetic phenomenon paramutation. The crosses of homozygous or heterozygous (e.g., F1) rogue plants with non-rogue (wild type) plants, produce exclusively rogue plants in the first and all subsequent generations. The fact that the wild phenotype disappears forever, is in clear contradiction with the Mendelian rules of inheritance, a situation that impedes the positional cloning of genes involved in this epigenetic phenomenon. One way of overcoming this obstacle is the identification of plant genotypes harboring naturally occurring or artificially induced neutral alleles, non-sensitive to paramutation. So far, such alleles have never been described for the pea rogue paramutation. Here, we report the induction via 1-ethyl-1-nitrosourea (ENU) mutagenesis of a non-rogue revertant mutant in the rogue cv. Progreta, and the completely unusual fixation of the induced non-rogue phenotype through several generations. The reversion of the methylation status of two previously identified differentially methylated genomic sequences in the induced non-rogue mutant, confirms that the rogue paramutation is accompanied by alterations in DNA methylation. Nevertheless, unexpectedly, the induced non-rogue mutant showed to be still sensitive to paramutation.

A novel test for annexin A5 M2 haplotyping in in vitro fertilization patients and preimplantation embryos

To develop a test for evaluating the annexin A5 M2 haplotype in invitro fertilization patients and preimplantation embryos. Test performance was measured by comparing Sanger sequencing of parental blood DNA and quantitative real-time polymerase chain reaction (qPCR) of saliva DNA, 3 fibroblast cell line 7-cell aliquots and their corresponding purified DNA, 123 trophectoderm biopsy samples, and DNA isolated from 1 embryonic stem cell line along with the Mendelian inheritance expectations, embryo Sanger sequencing, and single-nucleotide polymorphism (SNP) microarray-based linkage analysis. Preimplantation genetic testing laboratory research on IVF patient and embryo DNA. An assay was developed for the detection of the M2 haplotype on saliva samples of 6 invitro fertilization patients. In addition, 13 patients who underwent preimplantation genetic testing with data on parental and embryo biopsy DNA available for research use were evaluated. None. The concordance rates between Sanger sequencing, SNP array-based linkage analysis, and Mendelian inheritance expectations with qPCR. The concordance rate between Sanger sequencing and qPCR was 100% on parental blood DNA and saliva DNA. The sample concordance rate between all replicates of 7-cell aliquots was 100%. The sample concordance rate between 3 cell lines used to prepare 7-cell aliquots and purified genomic DNA was 100%. The concordance rate between qPCR and Sanger sequencing results from a single trophectoderm biopsy and isolated embryonic stem cell line was 100%. The concordance rate of trophectoderm biopsy qPCR results and expectations from Mendelian inheritance rules was 97%; however, when SNP array-based linkage analysis was included, the concordance rate reached 100%. This study resulted in the development of a convenient saliva collection method and qPCR-based genotyping method to screen for the M2 haplotype. In addition, a novel method for testing preimplantation embryos has been established, providing an alternative to the use of low molecular weight heparin, through selection of embryos without the M2 haplotype.

Clinical spectrum and management of imprinting disorders

Abstract Imprinting disorders are exceptional within the group of monogenic syndromes. They are associated with molecular changes affecting imprinted regions and usually do not follow the rules of Mendelian inheritance. They account for a relevant proportion of congenital disorders, especially within the syndromal growth entities with endocrine, neurological, and skeletal characteristics. In patients with imprinting disorders and accelerated growth, significant tumor risks have to be considered. The number of known imprinting disorders increases with the identification of new regions in which parentally imprinted genes are located. Imprinting disorders are caused by genomic pathogenic variants affecting imprinted genes, as well as by aberrant imprinting marks (epimutations) in the patients themselves. Additionally, maternal effect mutations have recently been identified that trigger secondary epimutations in the offspring. These maternal effect mutations explain not only imprinting disorders in their children, but also recurrent reproductive failure in the families. This review aims to provide an overview of the recent findings in 13 well-known imprinting disorders relating to clinical diagnosis, management and counseling.

Mitochondrial genetics revisited.

Mitochondrial genetics started decades ago with the discovery of yeast mutants that ignored the Mendelian rules of inheritance. Today, the many known DNA sequences of this second eukaryotic genome illustrate its eccentricity in terms of informational content and functional organisation, suggesting a yet incomplete understanding of its evolution. The hereditary transmission of mitochondrial alleles relies on complex mixes of molecular and cellular mechanisms in which recombination and limited sampling, two sources of rapid genetic changes, play central roles. It is also under the influence of invasive genetic elements whose inconstant distribution in mitochondrial genomes suggests rapid turnovers in evolving populations. This susceptibility to changes contrasts with the development of specific functional interactions between the mitochondrial and nuclear genetic compartments, a trend that is prone to limit the genetic exchanges between distinct lineages. It is perhaps this opposition and the discordant inheritance between mitochondrial and nuclear genomes that best explain the maintenance of a second genome and a second independent protein synthesising machinery in eukaryotic cells.

Gene Drives: Dynamics and Regulatory Matters-A Report from the Workshop "Evaluation of Spatial and Temporal Control of Gene Drives," April 4-5, 2019, Vienna.

Gene Drives are regarded as future tools with a high potential for population control. Due to their inherent ability to overcome the rules of Mendelian inheritance, gene drives (GD) may spread genes rapidly through populations of sexually reproducing organisms. A release of organisms carrying a GD would constitute a paradigm shift in the handling of genetically modified organisms because gene drive organisms (GDO) are designed to drive their transgenes into wild populations and thereby increase the number of GDOs. The rapid development in this field and its focus on wild populations demand a prospective risk assessment with a focus on exposure related aspects. Presently, it is unclear how adequate risk management could be guaranteed to limit the spread of GDs in time and space, in order to avoid potential adverse effects in socio‐ecological systems. The recent workshop on the “Evaluation of Spatial and Temporal Control of Gene Drives” hosted by the Institute of Safety/Security and Risk Sciences (ISR) in Vienna aimed at gaining some insight into the potential population dynamic behavior of GDs and appropriate measures of control. Scientists from France, Germany, England, and the USA discussed both topics in this meeting on April 4–5, 2019. This article summarizes results of the workshop.

Estimating the Genome-wide Mutation Rate with Three-Way Identity by Descent

The two primary methods for estimating the genome-wide mutation rate have been counting de novo mutations in parent-offspring trios and comparing sequence data between closely related species. With parent-offspring trio analysis it is difficult to control for genotype error, and resolution is limited because each trio provides information from only two meioses. Inter-species comparison is difficult to calibrate due to uncertainty in the number of meioses separating species, and it can be biased by selection and by changing mutation rates over time. An alternative class of approaches for estimating mutation rates that avoids these limitations is based on identity by descent (IBD) segments that arise from common ancestry within the past few thousand years. Existing IBD-based methods are limited to highly inbred samples, or lack robustness to genotype error and error in the estimated demographic history. We present an IBD-based method that uses sharing of IBD segments among sets of three individuals to estimate the mutation rate. Our method is applicable to accurately phased genotype data, such as parent-offspring trio data phased using Mendelian rules of inheritance. Unlike standard parent-offspring analysis, our method utilizes distant relationships and is robust to genotype error. We apply our method to data from 1,307 European-ancestry individuals in the Framingham Heart Study sequenced by the NHLBI TOPMed project. We obtain an estimate of 1.29× 10-8 mutations per base pair per meiosis with a 95% confidence interval of [1.02× 10-8, 1.56× 10-8].

Triturus newts

Ben Wielstra introduces Eurasian newts of the genus Triturus.

TriPoly: haplotype estimation for polyploids using sequencing data of related individuals.

Knowledge of haplotypes, i.e. phased and ordered marker alleles on a chromosome, is essential to answer many questions in genetics and genomics. By generating short pieces of DNA sequence, high-throughput modern sequencing technologies make estimation of haplotypes possible for single individuals. In polyploids, however, haplotype estimation methods usually require deep coverage to achieve sufficient accuracy. This often renders sequencing-based approaches too costly to be applied to large populations needed in studies of Quantitative Trait Loci. We propose a novel haplotype estimation method for polyploids, TriPoly, that combines sequencing data with Mendelian inheritance rules to infer haplotypes in parent-offspring trios. Using realistic simulations of both short and long-read sequencing data for banana (Musa acuminata) and potato (Solanum tuberosum) trios, we show that TriPoly yields more accurate progeny haplotypes at low coverages compared to existing methods that work on single individuals. We also apply TriPoly to phase Single Nucleotide Polymorphisms on chromosome 5 for a family of tetraploid potato with 2 parents and 37 offspring sequenced with an RNA capture approach. We show that TriPoly haplotype estimates differ from those of the other methods mainly in regions with imperfect sequencing or mapping difficulties, as it does not rely solely on sequence reads and aims to avoid phasings that are not likely to have been passed from the parents to the offspring. TriPoly has been implemented in Python 3.5.2 (also compatible with Python 2.7.3 and higher) and can be freely downloaded at https://github.com/EhsanMotazedi/TriPoly. Supplementary data are available at Bioinformatics online.

Haldane's The causes of evolution and the Modern Synthesis in evolutionary biology.

This paper argues that Haldane's The causes of evolution was the most important founding document in the emergence of the received view of evolutionary theory which is typically referred to as the Modern Synthesis. Whether or not this historical development is characterized as a synthesis (which remains controversial), this paper argues the most important component of the emergence of the received view consisted of showing how the formal rules of Mendelian inheritance are based on (or emerge from) the material basis of heredity established by classical genetics primarily through the experimental work on Drosophila genetics of the Morgan school in the 1910s and 1920s. This is one of the most important achievements of Haldane's book. Thus this paper rejects both (i) the view that the synthesis was a unification of biometry and Mendelism and (ii) the claim that it arose from work primarily done in the late 1930s and 1940s by naturalists rather than theoretical population and classical experimental geneticists.

Validating the use of non-invasively sourced DNA for population genetic studies using pedigree data

Abstract. Non-invasive genetic sampling has provided valuable ecological data for many species – data which may have been unobtainable using invasive sampling methods. However, DNA obtained non-invasively may be prone to increased levels of amplification failure and genotyping error. Utilizing genotype data from 32 pedigreed koalas, this study aimed to validate the reliability of final consensus genotypes obtained using DNA isolated from koala scats. Pedigree analysis, duplicate genotyping, analysis of mismatched loci and tests for null alleles were used to look for evidence of errors. All genetically confirmed parent–offspring relationships were found to follow Mendelian rules of inheritance. Duplicate genotypes matched in all cases and there was no evidence of null alleles. Related individuals always had different 12-marker genotypes having a minimum of three unique loci (in one full sibling pair), a mode of seven unique loci and a maximum of 11 unique loci. This study demonstrates the capacity of DNA recovered from koala scats to provide reliable genotypes that can unequivocally discriminate individuals and infer parentage, provided data are missing from no more than two loci. Validating data obtained using non-invasive sampling is an important step, allowing potential problems to be identified at an early stage.

Read-based phasing of related individuals

Motivation: Read-based phasing deduces the haplotypes of an individual from sequencing reads that cover multiple variants, while genetic phasing takes only genotypes as input and applies the rules of Mendelian inheritance to infer haplotypes within a pedigree of individuals. Combining both into an approach that uses these two independent sources of information—reads and pedigree—has the potential to deliver results better than each individually.Results: We provide a theoretical framework combining read-based phasing with genetic haplotyping, and describe a fixed-parameter algorithm and its implementation for finding an optimal solution. We show that leveraging reads of related individuals jointly in this way yields more phased variants and at a higher accuracy than when phased separately, both in simulated and real data. Coverages as low as 2× for each member of a trio yield haplotypes that are as accurate as when analyzed separately at 15× coverage per individual.Availability and Implementation: https://bitbucket.org/whatshap/whatshapContact: t.marschall@mpi-inf.mpg.de

Using Incomplete Trios to Boost Confidence in Family Based Association Studies.

Most currently available family based association tests are designed to account only for nuclear families with complete genotypes for parents as well as offspring. Due to the availability of increasingly less expensive generation of whole genome sequencing information, genetic studies are able to collect data for more families and from large family cohorts with the goal of improving statistical power. However, due to missing genotypes, many families are not included in the family based association tests, negating the benefits of large scale sequencing data. Here, we present the CIFBAT method to use incomplete families in Family Based Association Test (FBAT) to evaluate robustness against missing data. CIFBAT uses quantile intervals of the FBAT statistic by randomly choosing valid completions of incomplete family genotypes based on Mendelian inheritance rules. By considering all valid completions equally likely and computing quantile intervals over many randomized iterations, CIFBAT avoids assumption of a homogeneous population structure or any particular missingness pattern in the data. Using simulated data, we show that the quantile intervals computed by CIFBAT are useful in validating robustness of the FBAT statistic against missing data and in identifying genomic markers with higher precision. We also propose a novel set of candidate genomic markers for uterine related abnormalities from analysis of familial whole genome sequences, and provide validation for a previously established set of candidate markers for Type 1 diabetes. We have provided a software package that incorporates TDT, robustTDT, FBAT, and CIFBAT. The data format proposed for the software uses half the memory space that the standard FBAT format (PED) files use, making it efficient for large scale genome wide association studies.