The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma.

Multiple myeloma is the second most common hematological malignancy. Despite significant advances in treatment, relapse is common and carries a poor prognosis. Thus, it is critical to elucidate the genetic factors contributing to disease progression and drug resistance. Here, we carry out integrative clinical sequencing of 511 relapsed, refractory multiple myeloma (RRMM) patients to define the disease's molecular alterations landscape. The NF-κB and RAS/MAPK pathways are more commonly altered than previously reported, with a prevalence of 45-65% each. In the RAS/MAPK pathway, there is a long tail of variants associated with the RASopathies. By comparing our RRMM cases with untreated patients, we identify a diverse set of alterations conferring resistance to three main classes of targeted therapy in 22% of our cohort. Activating mutations in IL6ST are also enriched in RRMM. Taken together, our study serves as a resource for future investigations of RRMM biology and potentially informs clinical management.

Many gene and domain families have convergent fates following independent whole-genome duplication events in Arabidopsis, Oryza, Saccharomyces and Tetraodon.

Genome duplication is potentially a good source of new genes, but such genes take time to evolve. We have found a group of "duplication-resistant" genes, which have undergone convergent restoration to singleton status following several independent genome duplications. Restoration of duplication-resistant genes to singleton status could be important to long-term survival of a polyploid lineage. Angiosperms show more frequent polyploidization and a higher degree of duplicate gene preservation than other paleopolyploids, making them well-suited to further study of duplication-resistant genes.

Organization and evolution of resistance gene analogs in peanut.

The scarcity of genetic polymorphism in Arachis hypogaea (peanut), as in other monophyletic polyploid species, makes it especially vulnerable to nematode, bacterial, fungal, and viral pathogens. Although no disease resistance genes have been cloned from peanut itself, the conserved motifs in cloned resistance genes from other plant species provide a means to isolate and analyze similar genes from peanut. To survey the number, diversity, evolutionary history, and genomic organization of resistance gene-like sequences in peanut, we isolated 234 resistance gene analogs (RGAs) by using primers designed from conserved regions of different classes of resistance genes including NBS-LRR, and LRR-TM classes. Phylogenetic and sequence analyses were performed to explore evolutionary relationships both among peanut RGAs and with orthologous genes from other plant taxa. Fifty-six overgos designed from the RGA sequences on the basis of their phyletic association were applied to a peanut BAC library; 736 hybridizing BAC clones were fingerprinted and contigs were formed in order to gain insights into the genomic organization of these genes. All the fingerprinting gels were blotted and screened with the respective overgos in order to verify the authenticity of the hits from initial screens, and to explore the physical organization of these genes in terms of both copy number and distribution in the genome. As a result, we identified 250 putative resistance gene loci. A correlation was found between the phyletic positions of the sequences and their physical locations. The BACs isolated here will serve as a valuable resource for future applications, such as map-based cloning, and will help improve our understanding of the evolution and organization of these genes in the peanut genome.

Comparative physical mapping links conservation of microsynteny to chromosome structure and recombination in grasses.

Nearly finished sequences for model organisms provide a foundation from which to explore genomic diversity among other taxonomic groups. We explore genome-wide microsynteny patterns between the rice sequence and two sorghum physical maps that integrate genetic markers, bacterial artificial chromosome (BAC) fingerprints, and BAC hybridization data. The sorghum maps largely tile a genomic component containing 41% of BACs but 80% of single-copy genes that shows conserved microsynteny with rice and partially tile a nonsyntenic component containing 46% of BACs but only 13% of single-copy genes. The remaining BACs are centromeric (4%) or unassigned (8%). The two genomic components correspond to cytologically discernible "euchromatin" and "heterochromatin." Gene and repetitive DNA distributions support this classification. Greater microcolinearity in recombinogenic (euchromatic) than nonrecombinogenic (heterochromatic) regions is consistent with the hypothesis that genomic rearrangements are usually deleterious, thus more likely to persist in nonrecombinogenic regions by virtue of Muller's ratchet. Interchromosomal centromeric rearrangements may have fostered diploidization of a polyploid cereal progenitor. Model plant sequences better guide studies of related genomes in recombinogenic than nonrecombinogenic regions. Bridging of 35 physical gaps in the rice sequence by sorghum BAC contigs illustrates reciprocal benefits of comparative approaches that extend at least across the cereals and perhaps beyond.

Comparative genomics of Gossypium and Arabidopsis: unraveling the consequences of both ancient and recent polyploidy.

Both ancient and recent polyploidy, together with post-polyploidization loss of many duplicated gene copies, complicates angiosperm comparative genomics. To explore an approach by which these challenges might be mitigated, genetic maps of extant diploid and tetraploid cottons (Gossypium spp.) were used to infer the approximate order of 3016 loci along the chromosomes of their hypothetical common ancestor. The inferred Gossypium gene order corresponded more closely than the original maps did to a similarly inferred ancestral gene order predating an independent paleopolyploidization (alpha) in Arabidopsis. At least 59% of the cotton map and 53% of the Arabidopsis transcriptome showed correspondence in multilocus gene arrangements based on one or both of two software packages (CrimeStatII, FISH). Genomic regions in which chromosome structural rearrangement has been rapid (obscuring gene order correspondence) have also been subject to greater divergence of individual gene sequences. About 26%-44% of corresponding regions involved multiple Arabidopsis or cotton chromosomes, in some cases consistent with known, more ancient, duplications. The genomic distributions of multiple-locus probes provided early insight into the consequences for chromosome structure of an ancient large-scale duplication in cotton. Inferences that mitigate the consequences of ancient duplications improve leveraging of genomic information for model organisms in the study of more complex genomes.