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Spinal muscular atrophy (SMA) is a heritable neuromuscular disorder that causes degeneration of the alpha motor neurons from anterior horn cells in the spinal cord, which causes severe progressive hypotonia and muscular weakness. With a carrier frequency of 1 in 40–50 and an estimated incidence of 1 in 10,000 live births, SMA is the second most common autosomal recessive disorder. Affected individuals with SMA have a homozygous loss of function of the survival motor neuron gene SMN1 on 5q13 but keep the modifying SMN2 gene. The most common mutation causing SMA is a homozygous deletion of the SMN1 exon 7, which can be readily detected and used as a sensitive diagnostic test. Because SMN2 produces a reduced number of full-length transcripts, the number of SMN2 copies can modify the clinical phenotype and as such, becomes an essential predictive factor. Population-based SMA carrier screening identifies carrier couples that may pass on this genetic disorder to their offspring and allows the carriers to make informed reproductive choices or prepare for immediate treatment for an affected child. Three treatments have recently been approved by the Food and Drug Administration (FDA). Nusinersen increases the expression levels of the SMN protein using an antisense oligonucleotide to alter splicing of the SMN2 transcript. Onasemnogene abeparvovec is a gene therapy that utilizes an adeno-associated virus serotype 9 vector to increase low functional SMN protein levels. Risdiplam is a small molecule that alters SMN2 splicing in order to increase functional SMN protein. Newborn screening for SMA has been shown to be successful in allowing infants to be treated before the loss of motor neurons and has resulted in improved clinical outcomes. Several of the recommendations and guidelines in the review are based on studies performed in the United States.

In the Mexican axolotl (Ambystoma mexicanum), sex is determined by a single Mendelian factor, yet its sex chromosomes do not exhibit morphological differentiation typical of many vertebrate taxa that possess a single sex-determining locus. As sex chromosomes are theorized to differentiate rapidly, species with undifferentiated sex chromosomes provide the opportunity to reconstruct early events in sex chromosome evolution. Whole genome sequencing of 48 salamanders, targeted chromosome sequencing and in situ hybridization were used to identify the homomorphic sex chromosome that carries an A. mexicanum sex-determining factor and sequences that are present only on the W chromosome. Altogether, these sequences cover ~300 kb of validated female-specific (W chromosome) sequence, representing ~1/100,000th of the 32 Gb genome. Notably, a recent duplication of ATRX, a gene associated with mammalian sex-determining pathways, is one of few functional (non-repetitive) genes identified among these W-specific sequences. This duplicated gene (ATRW) was used to develop highly predictive markers for diagnosing sex and represents a strong candidate for a recently-acquired sex determining locus (or sexually antagonistic gene) in A. mexicanum.

The sea lamprey (Petromyzon marinus) represents one of the few vertebrate species known to undergo large-scale programmatic elimination of genomic DNA over the course of its normal development. Programmed genome rearrangements (PGRs) result in the reproducible loss of ~20% of the genome from somatic cell lineages during early embryogenesis. Studies of PGR hold the potential to provide novel insights related to the maintenance of genome stability during the cell cycle and coordination between mechanisms responsible for the accurate distribution of chromosomes into daughter cells, yet little is known regarding the mechanistic basis or cellular context of PGR in this or any other vertebrate lineage. Here we identify epigenetic silencing events that are associated with the programmed elimination of DNA and describe the spatiotemporal dynamics of PGR during lamprey embryogenesis. In situ analyses reveal that the earliest DNA methylation (and to some extent H3K9 trimethylation) events are limited to specific extranuclear structures (micronuclei) containing eliminated DNA. During early embryogenesis a majority of micronuclei (~60%) show strong enrichment for repressive chromatin modifications (H3K9me3 and 5meC). These analyses also led to the discovery that eliminated DNA is packaged into chromatin that does not migrate with somatically retained chromosomes during anaphase, a condition that is superficially similar to lagging chromosomes observed in some cancer subtypes. Closer examination of “lagging” chromatin revealed distributions of repetitive elements, cytoskeletal contacts and chromatin contacts that provide new insights into the cellular mechanisms underlying the programmed loss of these segments. Our analyses provide additional perspective on the cellular and molecular context of PGR, identify new structures associated with elimination of DNA and reveal that PGR is completed over the course of several successive cell divisions., Author Summary Lampreys possess a fascinating genome biology wherein large portions of the genome, including large numbers of genes, are programmatically deleted during development. The lamprey therefore represents a uniquely informative system with respect to several broad areas of biology, including genome stability/rearrangement, epigenetic silencing, and the establishment and maintenance of pluripotency. However, little is known regarding the cellular context or mechanism of deletion, partly due to the challenges of observing rearrangements in situ. Here we present analyses and new techniques that significantly advance our understanding of the subcellular context of programmed rearrangements and interactions between programmed deletion and canonical DNA silencing mechanisms. These analyses demonstrate that DNA elimination occurs earlier in embryogenesis than was previously recognized and reveal several new cellular and molecular aspects of programmed DNA loss. Specifically we show that eliminated DNA exhibits a unique migration pattern during cell division, is packaged into discreet subcellular structures later in the cell cycle, and undergoes epigenetic silencing through DNA and histone methylation. These observations provide new insight into the mechanisms underlying programmed DNA loss and suggest a functional link between programmed DNA loss and other, more conserved gene silencing pathways.