Domain duplication, divergence, and loss events in vertebrate Msx paralogs reveal phylogenomically informed disease markers

<p>Abstract</p> <p>Background</p> <p>Msx originated early in animal evolution and is implicated in human genetic disorders. To reconstruct the functional evolution of Msx and inform the study of human mutations, we analyzed the phylogeny and synteny of 46 metazoan Msx proteins and tracked the duplication, diversification and loss of conserved motifs.</p> <p>Results</p> <p>Vertebrate Msx sequences sort into distinct Msx1, Msx2 and Msx3 clades. The sister-group relationship between <it>MSX1 </it>and <it>MSX2 </it>reflects their derivation from the 4p/5q chromosomal paralogon, a derivative of the original "MetaHox" cluster. We demonstrate physical linkage between Msx and other MetaHox genes (<it>Hmx</it>, <it>NK1</it>, <it>Emx</it>) in a cnidarian. Seven conserved domains, including two Groucho repression domains (N- and C-terminal), were present in the ancestral Msx. In cnidarians, the Groucho domains are highly similar. In vertebrate Msx1, the N-terminal Groucho domain is conserved, while the C-terminal domain diverged substantially, implying a novel function. In vertebrate Msx2 and Msx3, the C-terminal domain was lost. MSX1 mutations associated with ectodermal dysplasia or orofacial clefting disorders map to conserved domains in a non-random fashion.</p> <p>Conclusion</p> <p>Msx originated from a MetaHox ancestor that also gave rise to Tlx, Demox, NK, and possibly EHGbox, Hox and ParaHox genes. Duplication, divergence or loss of domains played a central role in the functional evolution of Msx. Duplicated domains allow pleiotropically expressed proteins to evolve new functions without disrupting existing interaction networks. Human missense sequence variants reside within evolutionarily conserved domains, likely disrupting protein function. This phylogenomic evaluation of candidate disease markers will inform clinical and functional studies.</p

Zebrafish wnt9b Synteny and Expression During First and Second Arch, Heart, and Pectoral Fin Bud Morphogenesis

Roles for Wnt9b in craniofacial development are indicated by the cleft lip mutant phenotype observed in the A/WySn mouse strain,1 caused by a retrotransposon insertion mutation at the Wnt9b locus. Analyses of the zebrafish Wnt9b ortholog, wnt9b, were pursued to provide insight into early vertebrate craniofacial patterning events mediated by Wnt9b signaling. Zebrafish wnt9b cDNA clones were isolated and found to encode an open reading frame of 358 amino acids, with 68% amino acid identity to mouse Wnt9b and 70% amino acid identity to human WNT9B. Syntenic analyses demonstrated that wnt9b and wnt3 exist as a contiguous pair in amniote vertebrate species, and that these genes are separate in the zebrafish and Takifugu genomes. During the pharyngula period, a time of extensive growth and morphogenesis, zebrafish wnt9b exhibits discrete expression in dorsal and ventral first and second branchial arch tissues, the heart, and pectoral fin buds. These analyses suggest that in zebrafish, as in humans, wnt9b plays distinct roles in directing morphogenetic movements of developing branchial arch elements, and identify the zebrafish as a useful developmental model for the study of human craniofacial cleft lip and palate

FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate

Nonsyndromic orofacial clefts are a common complex birth defect caused by genetic and environmental factors and/or their interactions. A previous genome-wide linkage scan discovered a novel locus for cleft lip with or without cleft palate (CL/P) at 9q22–q33. To identify the etiologic gene, we undertook an iterative and complementary fine mapping strategy using family-based CL/P samples from Colombia, USA and the Philippines. Candidate genes within 9q22–q33 were sequenced, revealing 32 new variants. Concurrently, 397 SNPs spanning the 9q22–q33 2-LOD-unit interval were tested for association. Significant SNP and haplotype association signals (P = 1.45E − 08) narrowed the interval to a 200 kb region containing: FOXE1, C9ORF156 and HEMGN. Association results were replicated in CL/P families of European descent and when all populations were combined the two most associated SNPs, rs3758249 (P = 5.01E − 13) and rs4460498 (P = 6.51E − 12), were located inside a 70 kb high linkage disequilibrium block containing FOXE1. Association signals for Caucasians and Asians clustered 5′ and 3′ of FOXE1, respectively. Isolated cleft palate (CP) was also associated, indicating that FOXE1 plays a role in two phenotypes thought to be genetically distinct. Foxe1 expression was found in the epithelium undergoing fusion between the medial nasal and maxillary processes. Mutation screens of FOXE1 identified two family-specific missense mutations at highly conserved amino acids. These data indicate that FOXE1 is a major gene for CL/P and provides new insights for improved counseling and genetic interaction studies

Understanding the mental health of refugees: Trauma, stress, and the cultural context

At the end of 2016, there were a record-high 65.6 million people forcibly displaced according to the United Nations High Commissioner for Refugees (1). With 300,000 new people displaced in 2016, there were 20 people newly displaced every minute of 2016. Most refugees flee their homes with little time to prepare (2) and, in turn, frequently are ill-equipped with the financial, linguistic, and other resources needed to address the challenges of the journey that lies ahead. The nature of the pre-migration and flight experiences for refugees, which are frequently marked by fear, forced departure, and experiences of torture and trauma, distinguishes them from other voluntary migrants. Since 1975 approximately three million individuals have been resettled in the USA (approximately 2 million adults and 1 million children) (3); this represents a significant population to respond to clinically. Importantly, status as a forcibly displaced person seeking refuge is not in itself a psychiatric condition – refugee status is a sociopolitical phenomenon with common downstream psychosocial effects (4). As refugees resettle in third party countries, often after prolonged stays in refugee camps in a country or countries outside of their home, many experience mental health problems associated with past trauma, ongoing stress, or both. In order to effectively serve resettled refugee and migrant communities, mental health professionals including, researchers, clinicians, educators, and policy makers need to understand the impact of the refugee experience and cultural contexts on psychosocial functioning. This chapter will review the unique mental health challenges and culturally-responsive assessments and treatments targeting some of the world’s most vulnerable and resilient populations