Complex Inheritance Pattern Research Articles

Advancing Horticulture: The Role of Marker-Assisted Breeding in Crop Improvement

Marker-assisted breeding (MAB) is revolutionizing the cultivation of horticultural crops by enabling more accurate genetic selection of desired traits. Unlike traditional breeding methods, which depend heavily on selecting traits based on visible characteristics, a process often hindered by complex inheritance patterns and environmental influences, MAB uses molecular markers tied to specific genes. This allows breeders to more efficiently identify and choose plants with the desired genetic features. MAB has significantly accelerated the breeding process for crops with traits like disease resistance, higher yields, and enhanced nutritional and visual qualities. It also reduces the time needed for breeding cycles; while traditional methods may require multiple generations to achieve desired traits, MAB can confirm the presence of beneficial genes early, speeding up the development of improved varieties. This is particularly crucial in addressing challenges like climate change, where crops must quickly adapt to stressors such as drought, salinity, and temperature fluctuations. In essence, MAB represents a major advancement in horticultural crop development, increasing the precision and efficiency of breeding efforts. It also plays a vital role in creating crops suited to specific environmental and market needs, while helping tackle global issues like food security, climate change resilience, and sustainable farming. MAB positions horticulture to better meet evolving consumer expectations and agricultural demands.

Abstract 4134619: A Novel Missense Mutation in TNNT2 Gene in a Lebanese Pedigree With Ebstein Anomaly And Wolf-Parkinson-White Syndrome: A Case Report

Background: Ebstein anomaly (EA) is a rare congenital heart defect occurring in 1.2 to 5 in 100,000 live births, characterized by a downward displacement of the tricuspid valve, thin-walled right ventricle, and tricuspid valve regurgitation. It can present variably from asymptomatic cases to severe symptoms like arrhythmias and right-sided heart failure. EA is often associated with other anomalies such as interatrial communication and mitral valve prolapse. The condition can lead to accessory atrioventricular pathways, frequently resulting in Wolff-Parkinson-White syndrome (WPW), which involves abnormal heart electrical activity and increases the risk of sudden cardiac death. While the genetic basis of EA is not fully understood, it appears to involve multiple genes like FLNA and NKX2-5, MYH6, MYH7 suggesting a complex polygenic inheritance pattern. TNNT2 is known to be associated with Cardiomyopathy but has not been previously associated with EA and WPW. Case: In this report, we present findings from a lebanese family with EA, comprising 2 affected individuals. Whole exome sequencing in the affected individuals identified a pathogenic variant in the TNNT2 gene at coding strain position 260 (a missense mutation: C to T), resulting in the substitution of Proline with Leucine at position 87 in affected individuals (Figure 1). No variants were detected in any other candidate gene examined. Individuals I:1 and II:2 were found to be normal, with no EA findings on echocardiography. Methods: Whole exome sequencing in the patients involved collecting blood samples after obtaining consent. These samples were sent to Centogene lab, where genomic DNA is enzymatically fragmented. The regions of interest are then enriched using DNA capture probes, facilitating detailed genetic analysis. Results: The whole exome sequencing identified a heterozygous missense mutation in both the father and his daughter. This nonsynonymous variant is located on chromosome 1 (GRCh37) in the TNNT2 gene region. The specific variant, NM_001276345.1:c.260C>T p.(Pro87Leu), was found in both individuals. Conclusion: In conclusion, the genetic basis of EA is rather complex and remains poorly understood. It is established that mutations in the TNNT2 gene are linked to several cardiomyopathies, none of them overlap with the described phenotype of our patients. In this report, we therefore confirm the potential role of TNNT2 gene mutation in the genetic basis of familial EA with WPW.

Whole Exome-Wide Association Identifies Rare Variants in APC Associated with High-Risk Colorectal Cancer in the Middle East.

Background: Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enriched in high-impact rare alleles, which might play a crucial role in the etiology and susceptibility of CRC. Methods: In this study, an exome-wide association analysis was performed in 146 patients with high-risk CRC in the Middle East and 1395 healthy controls. The aim was to identify rare germline variants in coding regions and their splicing sites associated with high-risk CRC in the Middle Eastern population. Results: Rare inactivating variants (RIVs) in APC had the strongest association with high-risk CRC (6/146 in cases vs. 1/1395 in controls, OR = 59.7, p = 5.13 × 10-12), whereas RIVs in RIMS1, an RAS superfamily member, were significantly associated with high-risk CRC (5/146 case vs. 2/1395 controls, OR = 24.7, p = 2.03 × 10-8). Rare damaging variants in 17 genes were associated with high-risk CRC at the exome-wide threshold (p < 2.5 × 10-6). Based on the sequence kernel association test, nonsynonymous variants in six genes (TNXB, TAP2, GPSM3, ADGRG4, TMEM229A, and ANKRD33B) had a significant association with high-risk CRC. RIVs in APC-the most common high-penetrance genetic factor-were associated with patients with high-risk CRC in the Middle East. Individuals who inherited APC RIVs had an approximate 60-fold increased risk of developing CRC and were likely to develop the disease earlier. Conclusions: We identified new potential CRC predisposition variants in other genes that could play a role in CRC inheritance. However, large collaborative studies are needed to confirm the association of these variants with high-risk CRC. These results provide information for counseling patients with high-risk CRC and their families in our population.

Enhancing rice aroma through innovative approaches

Aromatic rice is used extensively in many different cuisines around the world for its wonderful aroma and cooking qualities. Aromatic rice varieties such as Basmati and non-Basmati fragrant rice have gained popularity in both domestic and foreign markets, despite their origins being predominantly in Southeast Asia and the Indian subcontinent. The primary gene responsible for rice aroma is the fgr/Badh2/Os2-AP, situated on chromosome 8 and encodes betaine aldehyde dehydrogenase 2 (Badh2). Key aroma compounds are attributed to over 500 volatiles. The primary aromatic molecule in rice, 2-acetyl-1-pyrroline (2-AP), accumulates as a result of mutations in this gene and gives rice its distinctive scent. Aroma is not decided by single compound rather it is decided by volatile profile and also by environmental factors. The identification of Quantitative Trait Loci (QTLs) linked to fragrance features on different chromosomes has improved our comprehension of the genetic processes behind rice scent. Advances in genetic engineering, particularly CRISPR/Cas9 and TALEN have facilitated the manipulation of the Badh2 gene, enhancing aroma profiles in rice. Additionally, gene silencing and introgression techniques have also proven in increasing 2-AP content. The review explores the biochemical properties and advancement of aromatic rice, emphasizing its complex inheritance patterns and potential for breeding improvement.

Identification of a genetic region linked to tolerance to MRSA infection using Collaborative Cross mice.

Staphylococcus aureus (S. aureus) colonizes humans asymptomatically but can also cause opportunistic infections, ranging from mild skin infections to severe life-threatening conditions. Resistance and tolerance are two ways a host can survive an infection. Resistance is limiting the pathogen burden, while tolerance is limiting the health impact of a given pathogen burden. In previous work, we established that collaborative cross (CC) mouse line CC061 is highly susceptible to Methicillin-resistant S. aureus infection (MRSA, USA300), while CC024 is tolerant. To identify host genes involved in tolerance after S. aureus infection, we crossed CC061 mice and CC024 mice to generate F1 and F2 populations. Survival after MRSA infection in the F1 and F2 generations was 65% and 55% and followed a complex dominant inheritance pattern for the CC024 increased survival phenotype. Colonization in F2 animals was more extreme than in their parents, suggesting successful segregation of genetic factors. We identified a Quantitative Trait Locus (QTL) peak on chromosome 7 for survival and weight change after infection. In this QTL, the WSB/EiJ (WSB) allele was present in CC024 mice and contributed to their MRSA tolerant phenotype. Two genes, C5ar1 and C5ar2, have high-impact variants in this region. C5ar1 and C5ar2 are receptors for the complement factor C5a, an anaphylatoxin that can trigger a massive immune response by binding to these receptors. We hypothesize that C5a may have altered binding to variant receptors in CC024 mice, reducing damage caused by the cytokine storm and resulting in the ability to tolerate a higher pathogen burden and longer survival.

Exome sequencing reveals neurodevelopmental genes in simplex consanguineous Iranian families with syndromic autism

Background and objectiveAutosomal recessive genetic disorders pose significant health challenges in regions where consanguineous marriages are prevalent. The utilization of exome sequencing as a frequently employed methodology has enabled a clear delineation of diagnostic efficacy and mode of inheritance within multiplex consanguineous families. However, these aspects remain less elucidated within simplex families.MethodsIn this study involving 12 unrelated simplex Iranian families presenting syndromic autism, we conducted singleton exome sequencing. The identified genetic variants were validated using Sanger sequencing, and for the missense variants in FOXG1 and DMD, 3D protein structure modeling was carried out to substantiate their pathogenicity. To examine the expression patterns of the candidate genes in the fetal brain, adult brain, and muscle, RT-qPCR was employed.ResultsIn four families, we detected an autosomal dominant gene (FOXG1), an autosomal recessive gene (CHKB), and two X-linked autism genes (IQSEC2 and DMD), indicating diverse inheritance patterns. In the remaining eight families, we were unable to identify any disease-associated genes. As a result, our variant detection rate stood at 33.3% (4/12), surpassing rates reported in similar studies of smaller cohorts. Among the four newly identified coding variants, three are de novo (heterozygous variant p.Trp546Ter in IQSEC2, heterozygous variant p.Ala188Glu in FOXG1, and hemizygous variant p.Leu211Met in DMD), while the homozygous variant p.Glu128Ter in CHKB was inherited from both healthy heterozygous parents. 3D protein structure modeling was carried out for the missense variants in FOXG1 and DMD, which predicted steric hindrance and spatial inhibition, respectively, supporting the pathogenicity of these human mutants. Additionally, the nonsense variant in CHKB is anticipated to influence its dimerization – crucial for choline kinase function – and the nonsense variant in IQSEC2 is predicted to eliminate three functional domains. Consequently, these distinct variants found in four unrelated individuals with autism are likely indicative of loss-of-function mutations.ConclusionsIn our two syndromic autism families, we discovered variants in two muscular dystrophy genes, DMD and CHKB. Given that DMD and CHKB are recognized for their participation in the non-cognitive manifestations of muscular dystrophy, it indicates that some genes transcend the boundary of apparently unrelated clinical categories, thereby establishing a novel connection between ASD and muscular dystrophy. Our findings also shed light on the complex inheritance patterns observed in Iranian consanguineous simplex families and emphasize the connection between autism spectrum disorder and muscular dystrophy. This underscores a likely genetic convergence between neurodevelopmental and neuromuscular disorders.

Precision diagnosis and therapeutic intervention of Alport syndrome

Alport syndrome is one of the most common inherited kidney diseases caused by mutations in the type Ⅳ collagen genes. It has a complex pattern of inheritance and diverse clinical manifestations, and severe cases will rapidly progress to end-stage kidney disease. With the rapid development of genetic testing technology, there is a deeper understanding of the genetic spectrum of Alport syndrome, the effectiveness of clinical therapies, and the prediction of disease prognosis. Therefore, the purpose of the article is to introduce the advances in the diagnosis and treatment of Alport syndrome, aiming to improve the early diagnosis and standardized treatment of this disease.

Family-based genetic analysis in schizophrenia by whole-exome sequence to identify rare pathogenic variants.

Schizophrenia (SCZ) is influenced by a combination of genetic and environmental factors. Although several studies have been conducted to identify the causative loci and genes, few of these loci or genes can be repeated due to the high phenotypic and genetic heterogeneity of disease, and their mechanisms are not fully understood. There may be some "missing heritability" that has not yet been found. In order to investigate the deleterious heritable mutations, whole-exome sequencing (WES) in pedigrees with SCZ was used in the current work. Two unrelated pedigrees with SCZ were recruited to perform WES. Genetic analysis was next performed to find potential variants in accordance with the prioritized strategy. Followed by genetic analysis to detect candidate variants according to the prioritized strategy. Next, a series of algorithms was used to predict the pathogenicity of variants. Sanger sequencing was finally conducted to verify the co-segregation. Recessive mutations in six genes (TFEB, SNAI2, TFAP2B, PRKDC, ST18 in Pedigree 1 and PKHD1L1 in Pedigree 2) that co-segregated with SCZ in two families were discovered through genetic analysis by WES. Sanger sequencing verified that all of the mutations in the affected siblings were homozygous. These results corroborated the hypothesis that SCZ exhibits strong heterogeneity and complex inheritance patterns. The newly discovered homozygous variations deepen our understanding of the mutation spectrum and offer more proof for the involvement of TFEB, SNAI2, TFAP2B, PRKDC, ST18, and PKHD1L1 in the development of SCZ.

Genotype Selection from Azide‐Induced Rice Mutants Using Multitrait Genotype–Ideotype Distance Index (MGIDI): Unveiling Promising Variants for Yield Improvement

Development of high‐yielding rice (Oryza sativa L.) is a crucial need for succeeding food security that needs the presence of great genetic variability to be used in breeding programs. Creating new variants through sodium azide mutagenesis can be a better alternative in advancing plant breeding issues. The generation and characterization of mutants represent an effective method for choosing genotypes with desired attributes. In this study, we focused on inducing mutations in the genetic base of a mega rice variety (BRRI dhan28) using sodium azide, evaluating the genetic diversity of the mutants, and identifying promising genotypes among the mutants using quantitative trait analysis and genetic criteria. The mutants exhibited substantial variation, as evidenced by descriptive statistics and analysis of variance. The estimated heritability and genetic advance indicated that nearly all traits had a high level of heritability and followed a complex pattern of inheritance. The strong correlations observed between grain yield and flag leaf length, branch panicle−1, grain panicle−1, 100‐grain weight, straw yield hill−1, and harvest index indicate that prioritizing these traits during selection could substantially improve other desirable characteristics. Additionally, we employed the principal component analysis which revealed that the first two components collectively accounted for 32.16% of the total variation, providing essential information about the genetic relatedness of the mutants. The Multitrait Genotype–Ideotype Distance Index (MGIDI) analysis revealed that out of 100 mutants, only eight exhibited noteworthy performance. These findings provide insights into the efficiency of azide in creating genetic variations in rice traits and offer valuable resources for future breeding programs aimed at developing high‐performing rice varieties.

Recent advances in the genetics of familial and sporadic ALS.

ALS shows complex genetic inheritance patterns. In about 5% to 10% of cases, there is a family history of ALS or a related condition such as frontotemporal dementia in a first or second degree relative, and for about 80% of such people a pathogenic gene variant can be identified. Such variants are also seen in people with no family history because of factor influencing the expression of genes, such as age. Genetic susceptibility factors also contribute to risk, and the heritability of ALS is between 40% and 60%. The genetic variants influencing ALS risk include single base changes, repeat expansions, copy number variants, and others. Here we review what is known of the genetic landscape and architecture of ALS.

Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases

BackgroundLong-read whole genome sequencing (lrWGS) has the potential to address the technical limitations of exome sequencing in ways not possible by short-read WGS. However, its utility in autosomal recessive Mendelian diseases is largely unknown.MethodsIn a cohort of 34 families in which the suspected autosomal recessive diseases remained undiagnosed by exome sequencing, lrWGS was performed on the Pacific Bioscience Sequel IIe platform.ResultsLikely causal variants were identified in 13 (38%) of the cohort. These include (1) a homozygous splicing SV in TYMS as a novel candidate gene for lethal neonatal lactic acidosis, (2) a homozygous non-coding SV that we propose impacts STK25 expression and causes a novel neurodevelopmental disorder, (3) a compound heterozygous SV in RP1L1 with complex inheritance pattern in a family with inherited retinal disease, (4) homozygous deep intronic variants in LEMD2 and SNAP91 as novel candidate genes for neurodevelopmental disorders in two families, and (5) a promoter SNV in SLC4A4 causing non-syndromic band keratopathy. Surprisingly, we also encountered causal variants that could have been identified by short-read exome sequencing in 7 families. The latter highlight scenarios that are especially challenging at the interpretation level.ConclusionsOur data highlight the continued need to address the interpretation challenges in parallel with efforts to improve the sequencing technology itself. We propose a path forward for the implementation of lrWGS sequencing in the setting of autosomal recessive diseases in a way that maximizes its utility.

Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity

BackgroundBiallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship.MethodsUsing an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity.ResultsA cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy.ConclusionsBased on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as “OGDHL-related disorders”.

Novel variants in TUBB8 gene cause multiple phenotypic abnormalities in human oocytes and early embryos

BackgroundThe genotype-phenotype relationships between TUBB8 variants and female infertility are difficult to clearly define due to the complex inheritance patterns and the highly heterogeneous phenotypes. This study aims to identify novel TUBB8 variants and relevant phenotypes in more infertile females.MethodsA total of 35 females with primary infertility were recruited from two reproductive centers and investigated for identifying variants in TUBB8. Pedigree analysis, in-silico analysis and molecular remodeling were performed to assess their clinical significance. The effects of the variants on human oocytes and embryos as well as HeLa cells were analyzed by morphological observations, immunostaining and Western blot.ResultsWe totally identified five novel variants (p.G13R, p.Y50C, p.T136I, p.F265V and p.T366A) and five previously reported variants (p.I4L, p.L42V, p.Q134*, p.V255M and p.V349I) in TUBB8 from 9 unrelated females with primary infertility. These variants were rare and highly conserved among different species, and were inherited in autosomal dominant/recessive patterns, or occurred de novo. In vitro functional assays in HeLa cells revealed that exogenous expression of mutant TUBB8 proteins caused different degrees of microtubule structural disruption. The existence of these pathogenic TUBB8 variants finally induced oocyte maturation arrest or morphological abnormalities, fertilization failure, cleavage failure, embryonic development defects and implantation failure in the affected females.ConclusionThese findings enriched the variant spectrum of TUBB8 gene and could contribute to optimize genetic counselling and clinical management of females with primary infertility.

An Outlook on GWAS with a Special Focus on Solanaceous Vegetable Crops – A Review

The commercial solanaceous group of vegetables viz., Tomato, Brinjal, Peppers, and Potatoes hold a prime position among all other vegetables in terms of cultivation and consumption worldwide. These vegetables are consumed fresh by all strata of people and are also used as raw materials in the processing industries. Hence, most plant breeders have a keen interest in the crop improvement of these crops emphasizing yield improvement, quality and nutraceuticals enrichment and imparting resistance to various biotic and abiotic stresses in accordance with climate change. Most of the desirable traits are polygenic in nature which may have a complex inheritance pattern. It is essential to have clear-cut knowledge of the expression frequencies of multiple genes/alleles governing a particular quantitative trait/phenotype, the methods employed to examine and comprehend the candidate genes governing one or various characteristics in plants are quantitative trait loci mapping and genome-wide association studies. In This review, we have discussed GWAS and its future perspectives and made efforts to tabulate the recent past works done in solanaceous vegetable crops using this approach. GWAS is a attractive strategy that constitutes an important advancement in genetic analysis and has unquestionably proven to be a useful tool in identifying candidate genes, which is justified in this article.

Impacts of salinity stress on crop plants: improving salt tolerance through genetic and molecular dissection.

Improper use of water resources in irrigation that contain a significant amount of salts, faulty agronomic practices such as improper fertilization, climate change etc. are gradually increasing soil salinity of arable lands across the globe. It is one of the major abiotic factors that inhibits overall plant growth through ionic imbalance, osmotic stress, oxidative stress, and reduced nutrient uptake. Plants have evolved with several adaptation strategies at morphological and molecular levels to withstand salinity stress. Among various approaches, harnessing the crop genetic variability across different genepools and developing salinity tolerant crop plants offer the most sustainable way of salt stress mitigation. Some important major genetic determinants controlling salinity tolerance have been uncovered using classical genetic approaches. However, its complex inheritance pattern makes breeding for salinity tolerance challenging. Subsequently, advances in sequence based breeding approaches and functional genomics have greatly assisted in underpinning novel genetic variants controlling salinity tolerance in plants at the whole genome level. This current review aims to shed light on physiological, biochemical, and molecular responses under salt stress, defense mechanisms of plants, underlying genetics of salt tolerance through bi-parental QTL mapping and Genome Wide Association Studies, and implication of Genomic Selection to breed salt tolerant lines.

Relationship between polymorphisms in the CD40 gene with the prevalence of breast cancer: A case-control study

Background. Breast cancer with a complex inheritance pattern is a major cause of cancer death among women worldwide. Single nucleotide polymorphisms (SNPs), the most common genetic variations, influence interindividual predisposition to disease and treatment outcomes with drugs. Evidence suggests that CD40 polymorphism contributes to pathogenesis of cancer. The co-stimulatory molecule CD40 plays a prominent role in immune regulation. This study aimed to test the association between polymorphisms in the CD40 gene and breast carcinogenesis in Arak, Iran. Methods. In this case-control study, three SNPs (rs1883832, rs4810485, rs3765459) were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. We included 80 patients with breast cancer and 80 healthy controls. Statistical analysis was performed by SPSS (version 26) using Chi-Squared test at P˂ 0.05. Results. Our data showed a statistically significant association between the two CD40 SNPs (1s1883832 and rs4810485) and breast cancer risk (P=0.038 and P=0.000, respectively). There was no significant association between rs3765459 and breast cancer risk (P=0.190). Conclusion. We witnessed that CD40 gene polymorphisms (rs1883832 and rs4810485) contributed to breast cancer. So, they are associated with breast cancer risk. Practical Implications. The obtained data revealed a significant relationship between the rs1883832 and rs4810485 polymorphisms and the risk of breast cancer. Thus, these polymorphisms could be used as biomarkers to predict breast cancer.

Critical Hypoglycemia in a Newborn with Pituitary Stalk Interruption Syndrome in Conjunction with 16p11.2 Deletion Syndrome and Duplication of Xp22.33/Yp11.32

This report is about a male newborn with pituitary stalk interruption syndrome (PSIS) who presented with apneic episodes associated with critical hypoglycemia at 3 hours of life (HOL). The onset of manifestations of PSIS varies in timing with the mean age of presentation between 4 and 5 years of age. The cause is unclear, but birth-related complications are considered potential factors. There is also a growing recognition of increasingly complex PSIS inheritance patterns. Further genetic workup for our patient revealed the deletion of the 16p11.2 gene with duplication of Xp22.33/Yp11.32. This is the first case report that describes PSIS in conjunction with these mutations, so the clinical correlation is unknown. However, 16p11.2 deletion is known to be associated with epilepsy and brain abnormalities. Additionally, duplication of Xp22.33/Yp11.32 is noted to be associated with short stature.

GWAS using low-pass whole genome sequence reveals a novel locus in canine congenital idiopathic megaesophagus.

Congenital idiopathic megaesophagus (CIM) is a gastrointestinal disorder of dogs wherein the esophagus is dilated and swallowing activity is reduced, causing regurgitation of ingesta. Affected individuals experience weight loss and malnourishment and are at risk for aspiration pneumonia, intussusception, and euthanasia. Great Danes have among the highest incidences of CIM across dog breeds, suggesting a genetic predisposition. We generated low-pass sequencing data for 83 Great Danes and used variant calls to impute missing whole genome single-nucleotide variants (SNVs) for each individual based on haplotypes phased from 624 high-coverage dog genomes, including 21 Great Danes. We validated the utility of our imputed data set for genome-wide association studies (GWASs) by mapping loci known to underlie coat phenotypes with simple and complex inheritance patterns. We conducted a GWAS for CIM with 2,010,300 SNVs, identifying a novel locus on canine chromosome 1 (P-val = 2.76 × 10-10). Associated SNVs are intergenic or intronic and are found in two clusters across a 1.7-Mb region. Inspection of coding regions in high-coverage genomes from affected Great Danes did not reveal candidate causal variants, suggesting that regulatory variants underlie CIM. Further studies are necessary to assess the role of these non-coding variants.

A tale of two paths: The evolution of mitochondrial recombination in bivalves with doubly uniparental inheritance.

In most animals, mitochondrial DNA is strictly maternally inherited and non-recombining. One exception to this pattern is called doubly uniparental inheritance (DUI), a phenomenon involving the independent transmission of female and male mitochondrial genomes. DUI is known only from the molluskan class Bivalvia. The phylogenetic distribution of male-transmitted mitochondrial DNA (M mtDNA) in bivalves is consistent with several evolutionary scenarios, including multiple independent gains, losses, and varying degrees of recombination with female-transmitted mitochondrial DNA (F mtDNA). In this study, we use phylogenetic methods to test M mtDNA origination hypotheses and infer the prevalence of mitochondrial recombination in bivalves with DUI. Phylogenetic modeling using site concordance factors supported a single origin of M mtDNA in bivalves coupled with recombination acting over long evolutionary timescales. Ongoing mitochondrial recombination is present in Mytilida and Venerida, which results in a pattern of concerted evolution of F mtDNA and M mtDNA. Mitochondrial recombination could be favored to offset the deleterious effects of asexual inheritance and maintain mitonuclear compatibility across tissues. Cardiida and Unionida have gone without recent recombination, possibly due to an extension of the COX2 gene in male mitochondrial DNA. The loss of recombination could be connected to the role of M mtDNA in sex determination or sexual development. Our results support that recombination events may occur throughout the mitochondrial genomes of DUI species. Future investigations may reveal more complex patterns of inheritance of recombinants, which could explain the retention of signal for a single origination of M mtDNA in protein-coding genes.

P519: Evidence of complex inheritance patterns in limb-girdle and other muscular dystrophies: Synergistic heterozygosity and multigenic inheritance

P519: Evidence of complex inheritance patterns in limb-girdle and other muscular dystrophies: Synergistic heterozygosity and multigenic inheritance