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      NK2 homeobox gene cluster: Functions and roles in human diseases

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          Abstract

          NK2 genes ( NKX2 gene cluster in humans) encode for homeodomain-containing transcription factors that are conserved along the phylogeny. According to the most detailed classifications, vertebrate NKX2 genes are classified into two distinct families, NK2.1 and NK2.2. The former is constituted by NKX2-1 and NKX2-4 genes , which are homologous to the Drosophila scro gene; the latter includes NKX2-2 and NKX2-8 genes, which are homologous to the Drosophila vnd gene. Conservation of these genes is not only related to molecular structure and expression, but also to biological functions. In Drosophila and vertebrates, NK2 genes share roles in the development of ventral regions of the central nervous system. In vertebrates, NKX2 genes have a relevant role in the development of several other organs such as the thyroid, lung, and pancreas. Loss-of-function mutations in NKX2-1 and NKX2-2 are the monogenic cause of the brain-lung-thyroid syndrome and neonatal diabetes, respectively. Alterations in NKX2-4 and NKX2-8 genes may play a role in multifactorial diseases, autism spectrum disorder, and neural tube defects, respectively. NKX2-1, NKX2-2, and NKX2-8 are expressed in various cancer types as either oncogenes or tumor suppressor genes. Several data indicate that evaluation of their expression in tumors has diagnostic and/or prognostic value.

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          Most cited references119

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          Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours.

          Ewing's sarcoma and related subtypes of primitive neuroectodermal tumours share a recurrent and specific t(11;22) (q24;q12) chromosome translocation, the breakpoints of which have recently been cloned. Phylogenetically conserved restriction fragments in the vicinity of EWSR1 and EWSR2, the genomic regions where the breakpoints of chromosome 22 and chromosome 11 are, respectively, have allowed identification of transcribed sequences from these regions and has indicated that a hybrid transcript might be generated by the translocation. Here we use these fragments to screen human complementary DNA libraries to show that the translocation alters the open reading frame of an expressed gene on chromosome 22 gene by substituting a sequence encoding a putative RNA-binding domain for that of the DNA-binding domain of the human homologue of murine Fli-1.
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            Rapid subfunctionalization accompanied by prolonged and substantial neofunctionalization in duplicate gene evolution.

            Gene duplication is the primary source of new genes. Duplicate genes that are stably preserved in genomes usually have divergent functions. The general rules governing the functional divergence, however, are not well understood and are controversial. The neofunctionalization (NF) hypothesis asserts that after duplication one daughter gene retains the ancestral function while the other acquires new functions. In contrast, the subfunctionalization (SF) hypothesis argues that duplicate genes experience degenerate mutations that reduce their joint levels and patterns of activity to that of the single ancestral gene. We here show that neither NF nor SF alone adequately explains the genome-wide patterns of yeast protein interaction and human gene expression for duplicate genes. Instead, our analysis reveals rapid SF, accompanied by prolonged and substantial NF in a large proportion of duplicate genes, suggesting a new model termed subneofunctionalization (SNF). Our results demonstrate that enormous numbers of new functions have originated via gene duplication.
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              Preservation of duplicate genes by complementary, degenerative mutations.

              The origin of organismal complexity is generally thought to be tightly coupled to the evolution of new gene functions arising subsequent to gene duplication. Under the classical model for the evolution of duplicate genes, one member of the duplicated pair usually degenerates within a few million years by accumulating deleterious mutations, while the other duplicate retains the original function. This model further predicts that on rare occasions, one duplicate may acquire a new adaptive function, resulting in the preservation of both members of the pair, one with the new function and the other retaining the old. However, empirical data suggest that a much greater proportion of gene duplicates is preserved than predicted by the classical model. Here we present a new conceptual framework for understanding the evolution of duplicate genes that may help explain this conundrum. Focusing on the regulatory complexity of eukaryotic genes, we show how complementary degenerative mutations in different regulatory elements of duplicated genes can facilitate the preservation of both duplicates, thereby increasing long-term opportunities for the evolution of new gene functions. The duplication-degeneration-complementation (DDC) model predicts that (1) degenerative mutations in regulatory elements can increase rather than reduce the probability of duplicate gene preservation and (2) the usual mechanism of duplicate gene preservation is the partitioning of ancestral functions rather than the evolution of new functions. We present several examples (including analysis of a new engrailed gene in zebrafish) that appear to be consistent with the DDC model, and we suggest several analytical and experimental approaches for determining whether the complementary loss of gene subfunctions or the acquisition of novel functions are likely to be the primary mechanisms for the preservation of gene duplicates. For a newly duplicated paralog, survival depends on the outcome of the race between entropic decay and chance acquisition of an advantageous regulatory mutation. Sidow 1996(p. 717) On one hand, it may fix an advantageous allele giving it a slightly different, and selectable, function from its original copy. This initial fixation provides substantial protection against future fixation of null mutations, allowing additional mutations to accumulate that refine functional differentiation. Alternatively, a duplicate locus can instead first fix a null allele, becoming a pseudogene. Walsh 1995 (p. 426) Duplicated genes persist only if mutations create new and essential protein functions, an event that is predicted to occur rarely. Nadeau and Sankoff 1997 (p. 1259) Thus overall, with complex metazoans, the major mechanism for retention of ancient gene duplicates would appear to have been the acquisition of novel expression sites for developmental genes, with its accompanying opportunity for new gene roles underlying the progressive extension of development itself. Cooke et al. 1997 (p. 362)
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                Author and article information

                Contributors
                Journal
                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                2352-4820
                2352-3042
                11 October 2022
                September 2023
                11 October 2022
                : 10
                : 5
                : 2038-2048
                Affiliations
                [a ]Dipartimento di Area Medica, Università degli Studi di Udine, Udine 33100, Italy
                [b ]Istituto di Genetica Medica, Azienda Sanitaria Universitaria Friuli Centrale, Udine 33100, Italy
                Author notes
                []Corresponding author. Dipartimento di Area Medica (DAME), Università degli Studi di Udine, Via Colugna 50, Udine 33100, Italy. catia.mio@ 123456uniud.it
                Article
                S2352-3042(22)00262-8
                10.1016/j.gendis.2022.10.001
                10363584
                37492711
                05dbc9cb-5fac-416f-b5dd-eff0baa28512
                © 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 8 June 2022
                : 15 September 2022
                : 1 October 2022
                Categories
                Review Article

                drosophila melanogaster,evolutionary conservation,homeobox,homeotic genes,nk2 genes

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