Identification and annotation of centromeric hypomethylated regions with CDR-Finder.

Motivation: Centromeres are chromosomal regions historically understudied with sequencing technologies due to their repetitive nature and short-read mapping limitations. However, recent improvements in long-read sequencing allow for the investigation of complex regions of the genome at the sequence and epigenetic levels.

Results: Here, we present Centromere Dip Region (CDR)-Finder: a tool to identify regions of hypomethylation within the centromeres of high-quality, contiguous genome assemblies.

Complete chromosome 21 centromere sequences from a Down syndrome family reveal size asymmetry and differences in kinetochore attachment.

Down syndrome is the most common form of human intellectual disability caused by precocious segregation and nondisjunction of chromosome 21. Differences in centromere structure have been hypothesized to play a potential role in this process in addition to the well-established risk of advancing maternal age. Using long-read sequencing, we completely sequenced and assembled the centromeres from a parent-child trio where Trisomy 21 arose in the child as a result of a meiosis I error.

Applications of long-read sequencing to Mendelian genetics.

Advances in clinical genetic testing, including the introduction of exome sequencing, have uncovered the molecular etiology for many rare and previously unsolved genetic disorders, yet more than half of individuals with a suspected genetic disorder remain unsolved after complete clinical evaluation. A precise genetic diagnosis may guide clinical treatment plans, allow families to make informed care decisions, and permit individuals to participate in N-of-1 trials; thus, there is high interest in developing new tools and techniques to increase the solve rate. Long-read sequencing (LRS) is a promising technology for both increasing the solve rate and decreasing the amount of time required to make a precise genetic diagnosis.

A de novo paradigm for male infertility.

De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents.

Exome sequencing reveals variants in known and novel candidate genes for severe sperm motility disorders.

Study Question: What are the causative genetic variants in patients with male infertility due to severe sperm motility disorders?

Summary Answer: We identified high confidence disease-causing variants in multiple genes previously associated with severe sperm motility disorders in 10 out of 21 patients (48%) and variants in novel candidate genes in seven additional patients (33%).

What Is Known Already: Severe sperm motility disorders are a form of male infertility characterised by immotile sperm often in combination with a spectrum of structural abnormalities of the sperm flagellum that do not affect viability. Currently, depending on the clinical sub-categorisation, up to 50% of causality in patients with severe sperm motility disorders can be explained by pathogenic variants in at least 22 genes.

Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility.

Asthenoteratozoospermia characterized by multiple morphological abnormalities of the flagella (MMAF) has been identified as a sub-type of male infertility. Recent progress has identified several MMAF-associated genes with an autosomal recessive inheritance in human affected individuals, but the etiology in approximately 40% of affected individuals remains unknown. Here, we conducted whole-exome sequencing (WES) and identified hemizygous missense variants in the X-linked CFAP47 in three unrelated Chinese individuals with MMAF.

Analysis of human ES cell differentiation establishes that the dominant isoforms of the lncRNAs RMST and FIRRE are circular.

Background: Circular RNAs (circRNAs) are predominantly derived from protein coding genes, and some can act as microRNA sponges or transcriptional regulators. Changes in circRNA levels have been identified during human development which may be functionally important, but lineage-specific analyses are currently lacking. To address this, we performed RNAseq analysis of human embryonic stem (ES) cells differentiated for 90 days towards 3D laminated retina.