Reclassification of a frequent African‐origin variant from PMS2 to the pseudogene PMS2CL

Genomic analysis has become a mainstay in the investigation of cancer patients, especially for those suspected of harboring a heritable cancer predisposition syndrome. With ubiquitous short‐read next‐generation sequencing (NGS) technologies, these analyses can be complicated by the inappropriate alignment of variants to homologous genomic regions or pseudogenes. Using distinct primer sets specific to the gene and pseudogene, a nonspecific primer set, and a highly gene‐specific long‐range polymerase chain reaction primer set, we have shown that in at least a subset of patients, the common African PMS2 variant NM_000535.5:c.2182_2184delACTinsG, classified as pathogenic in ClinVar, has been incorrectly assigned to PMS2 from its well‐documented pseudogene, PMS2CL. This result is not only important for patients but also highlights a weakness in short‐read NGS technologies and the racial inequity in genomic analysis.     

Gene inactivation and its implications for annotation in the era of personal genomics

The first wave of personal genomes documents how no single individual genome contains the full complement of functional genes. Here, we describe the extent of variation in gene and pseudogene numbers between individuals arising from inactivation events such as premature termination or aberrant splicing due to single-nucleotide polymorphisms. This highlights the inadequacy of the current reference sequence and gene set. We present a proposal to define a reference gene set that will remain stable as more individuals are sequenced. In particular, we recommend that the ancestral allele be used to define the reference sequence from which a core human reference gene annotation set can be derived. In addition, we call for the development of an expanded gene set to include human-specific genes that have arisen recently and are absent from the ancestral set.     

Presence of a 16S rRNA pseudogene in the bi-molecular plastid genome of the primitive brown alga Pylaiella littoralis. Evolutionary implications

Summary The plastid genome of the brown alga Pylaiella littoralis (L.) Kjellm. is composed of two different circular DNA molecules: the largest carries two rrn operons, and the smallest, only one copy of both 16S and 23S rDNAs. 16S rDNA copies located on both molecules have been cloned and their nucleotide sequences determined: they are 65% homologous to one another. The expression of these genes was assayed by hybridizing in vivo labelled P. littoralis rRNAs to both clones, and specific oligonucleotides to total RNA from P. littoralis. Results indicate that the 16S rDNA copy located on the small molecule is a pseudogene. Comparisons of the functional gene with other 16S rRNA genes shows that chloroplasts from green plants emerged earlier from the cyanobacterial lineage than Euglena gracilis and Pylaiella littoralis plastids.     

Genome-wide identification of pseudogenes capable of disease-causing gene conversion

Pseudogenes are remnants of gene duplication (nonprocessed pseudogenes) and retrotransposition (processed pseudogenes) events. This study describes methods for identifying gene conversion candidates from predicted pseudogenes. Pseudogenes may accumulate and harbor sequence variations over time that become disease-causing mutations when transferred to genes by gene conversion. A total of 14,476 pseudogenes were identified, including 3,426 nonprocessed pseudogenes. In addition, 1,945 nonprocessed pseudogenes that are localized near their progenitor gene were evaluated for their possible role in gene conversion and disease. All 11 known, human cases of gene conversion (with deleterious effects) involving pseudogenes were successfully identified by these methods. Among the pseudogenes identified is a retinitis pigmentosa 9 (RP9) pseudogene that carries a c.509A>G mutation which produces a p.Asp170Gly substitution that is associated with the RP9 form of autosomal dominant retinitis pigmentosa (adRP). The c.509A>G mutation in RP9 is a previously unrecognized example of gene conversion between the progenitor gene and its pseudogene. Notably, two processed pseudogenes also contain mutations associated with diseases. An inosine monophosphate dehydrogenase 1 (IMPDH1) pseudogene carries a c.676G>A mutation that produces a p.Asp226Asn substitution that causes the retinitis pigmentosa 10 (RP10) form of adRP; and a phosphoglycerate kinase 1 (PGK1) pseudogene (PGK1P1) carries a c.837T>C mutation that produces a p.Ile252Thr substitution that is associated with a phosphoglycerate kinase deficiency. Ranking of nonprocessed pseudogenes as candidates for gene conversion was also performed based on the sequence characteristics of published cases of pseudogene-mediated gene conversion. All results and tools produced by this study are available for download at: http://genome.uiowa.edu/pseudogenes.     

Glucocerebrosidase (Gaucher disease)

Gaucher disease is the most common glycolipid storage disorder, characterized by storage of the glycolipid, glucocerebroside in the liver, spleen, and marrow. The most prevalent form of Gaucher disease is designated type I (MIM 230800). Patients with type I disease may have hepatomegaly, splenomegaly, bone lesions, and less commonly, lung disease, but are free of neurological involvement. Types II (MIM 230900) and III (MIM 2310000), the acute infantile and juvenile forms, respectively, of Gaucher disease, are characterized by the fact that the central nervous system is affected. © 1996 Wiley-Liss, Inc.     

双同源盒假基因9在肿瘤发生发展中的作用及机制

长链非编码RNA（long non-coding RNA,lncRNA）是由RNA聚合酶II转录的长度大于200个核苷酸并且不编码蛋白的RNA,不仅可以调控人体的生长发育过程而且在肿瘤的发生发展中也发挥重要作用。双同源盒假基因9（double homeobox A pseudogene 9,DUXAP9）作为一种在诸多肿瘤中表达异常上调的lncRNA,可以通过内源性竞争RNA、招募蛋白、介导上皮间质转化以及激活信号通路等方式来调控肿瘤的恶性生物学行为。对DUXAP9的促癌作用机制进行深入研究有助于相关肿瘤的早期诊断和靶向治疗。本文就DUXAP9在肿瘤发生发展中的作用及机制作一综述。