On closing the inopportune gap with consistency transformation and iterative refinement.

The problem of aligning multiple biological sequences has fascinated scientists for a long time. Over the last four decades, tens of heuristic-based Multiple Sequence Alignment (MSA) tools have been proposed, the vast majority being built on the concept of Progressive Alignment. It is known, however, that this approach suffers from an inherent drawback regarding the inadvertent insertion of gaps when aligning sequences. Two well-known corrective solutions have frequently been adopted to help mitigate this: Consistency Transformation and Iterative Refinement. This paper takes a tool-independent technique-oriented look at the alignment quality benefits of these two strategies using problem instances from the HOMSTRAD and BAliBASE benchmarks. Eighty MSA aligners have been used to compare 4 classes of heuristics: Progressive Alignments, Iterative Alignments, Consistency-based Alignments, and Consistency-based Progressive Alignments with Iterative Refinement. Statistically, while both Consistency-based classes are better for alignments with low similarity, for sequences with higher similarity, the differences between the classes are less clear. Iterative Refinement has its own drawbacks resulting in there being statistically little advantage for Progressive Aligners to adopt this technique either with Consistency Transformation or without. Nevertheless, all 4 classes are capable of bettering each other, depending on the instance problem. This further motivates the development of MSA frameworks, such as the one being developed for this research, which simultaneously contemplate multiple classes and techniques in their attempt to uncover better solutions.

How Ancestry Influences the Chances of Finding Unrelated Donors: An Investigation in Admixed Brazilians.

A match of HLA loci between patients and donors is critical for successful hematopoietic stem cell transplantation. However, the extreme polymorphism of HLA loci - an outcome of millions of years of natural selection - reduces the chances that two individuals will carry identical combinations of multilocus HLA genotypes. Further, HLA variability is not homogeneously distributed throughout the world: African populations on average have greater variability than non-Africans, reducing the chances that two unrelated African individuals are HLA identical. Here, we explore how self-identification (often equated with "ethnicity" or "race") and genetic ancestry are related to the chances of finding HLA compatible donors in a large sample from Brazil, a highly admixed country. We query REDOME, Brazil's Bone Marrow Registry, and investigate how different criteria for identifying ancestry influence the chances of finding a match. We find that individuals who self-identify as "Black" and "Mixed" on average have lower chances of finding matches than those who self-identify as "White" (up to 57% reduction). We next show that an individual's African genetic ancestry, estimated using molecular markers and quantified as the proportion of an individual's genome that traces its ancestry to Africa, is strongly associated with reduced chances of finding a match (up to 60% reduction). Finally, we document that the strongest reduction in chances of finding a match is associated with having an MHC region of exclusively African ancestry (up to 75% reduction). We apply our findings to a specific condition, for which there is a clinical indication for transplantation: sickle-cell disease. We show that the increased African ancestry in patients with this disease leads to reduced chances of finding a match, when compared to the remainder of the sample, without the condition. Our results underscore the influence of ancestry on chances of finding compatible HLA matches, and indicate that efforts guided to increasing the African component of registries are necessary.