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In biology, evolution is the gradual change in genetic material of a population of organisms through time. Over thousands of years, mammalian development has continued to evolve through genetically inherited traits passed down from many generations. Specific genes that were inherited lead to mammalian speciation and the expression of some known developmental genes. These developmental genes are found in the “Homeobox”, which is a specific DNA sequence in an individual's genome that regulate patterns of development. Within these homeoboxes are individual Hox genes. Hox genes are a group of transcription factor genes that stipulate the anterior-posterior axis and segmentation of organisms during early embryonic development, which are critical for the correct number and placement of anatomical structures. Hox genes are analogous to a morphological blueprint, which provides the instructions to form parts of the abdomen, thorax, and head of an organism. During my research, I have acquired an interest in the evolution of homeotic genes in human development, comparative to vertebrate homologous structures. Using other vertebrate hox gene examples, I will also exhibit an outlook on the evolution of reproductive structures in humans. “There are difference in limb morphology and in developmental mechanisms between the chick and the mouse. These differences are likely attributable to adaptable evolution and phenogenetic drift since the split between the mammalian and reptilian lineages over 220 million years ago.” (Wyngaarden, and Hopyan 225-233).
In genetic research, different forms and functions of these Hox genes are commonly explored in fruit flies, mice and other vertebrae. “Vertebrates, including mice, have Hox genes that are homologous to those of the fly, and these genes are clustered in discrete locations with a 3'-to-5' order reflecting an anterior to posterior order of expression. There are numerous differences between the mouse and fly Hox genes. One obvious difference is that there are more Hox genes on the 5' side of the mouse segment. These differences correspond to expression in the tail, and flies do not have anything comparable to the chordate tail. Another difference is that, in the mouse, there are four banks of Hox genes: HoxA, HoxB, HoxC, and HoxD. Vertebrates have these parallel, overlapping sets of Hox genes, which suggest that morphology could be a product of expression of the genes in the four Hox clusters.”(myers). Throughout evolutionary history, homeotic genes have become more complex. Fly and mouse hox genes had a common ancestor about 500 million years ago. The mouse hox genes for example are associated with many vertebrate hox genes, but aren't identical. “Homeobox genes must have originated early in eukaryotic evolution, because they are found in animals, plants and fungi. The complexity of the homeodomain sequence implies that a single origin is likely. The first homeobox gene presumably evolved in an early eukaryotic species, and extensive gene duplication events then gave rise to the vast diversity of homebox genes observed today. It is still unclear exactly how many functional homeobox genes exist in the human genome” (Holland, and Takahashi 484-490). The homeobox genes of humans are classified into gene families with each gene family containing one to several genes. The use of molecular phylogenetics to determine the origin of homeobox gene families would be a difficult process because during meiosis a chromosomal crossover results in the duplication of cells and genes. “Consider two genes that originated by tandem duplication early in animal evolution: genes A and B. In an ancient bilaterian animal, these genes would have been adjacent, reflecting their origin by tandem gene duplication. During vertebrate evolution, the genomic region containing these two linked genes would have been duplicated once or twice, to yield at least two, and more likely four chromosomes, each with an A and a B family gene. Loss of an A gene from one chromosome, and a B gene from another chromosome would now leave A genes and B genes on different chromosomes. This pattern would obscure their ancient origins by tandem duplication. Such patterns, and indeed far more complicated arrangements are common-place in the human genome. As a consequence, it is very difficult to deduce the evolutionary history of homeobox genes from human linkage data alone.” (Holland, and Takahashi 484-490).
Homeobox or Hox gene complexes determine the anterior–posterior body axis in animals. The organization of these complexes is associated with the expression and function of bodily segments along the axis. In a related study, the chromosomal organization and function similarities are preserved in all bilaterians are investigated. “While such an extreme conservation of several hundred nucleotides over half a billion years in a region that does not code for any known proteins certainly implicates essential role for such sequences, probably in he regulation of Hox D complex, no known regulatory element requires such extreme conservation extending up to hundreds of base pairs. It is, therefore, likely that these elements could be components of a novel mechanism common to all vertebrates that regulates this gene complex. We are tempted to suggest that such a strongly conserved region from fish to human linked to a gene complex that is known to determine body axis formation may be the key determinant of molecular basis of early ontogeny. Early embryos of all vertebrates show striking similarity and we suggest that these elements may control the early expression pattern of the embryo shape. The gradient of conservation seen in this region from fish to human may further signify the evolutionary history of this locus and diversification of the morphological features along the anterior-posterior body axis of the vertebrate classes.” (Sabarinadh, Subramanian, Tripathi, and Mishra).
In a recent experiment, scientists dissociate the differences between limb function and limb development. Limbs of 189 mammals were examined to test if limb porportions are controlled by biomechanical principles. These scientists believe that a relationship exists between the first and third elements of each limb, while the middle element is less involved. “These two conditions, common development and common function are met in the serially homologuous limb elements of all quadruped tetrapods except marsupial and placental mammals. During the evolution of therian mammals, fore and hindlimbs underwent a fundamental reorganization that caused a dissociation between serial and functional homologues as the evolutionary transformation from the ancestral sprawled to the derived parasagittal condition, was different in the fore and hindlimbs.” (Schmidt, and Fischer 749-766).
Focusing on evolutionary development of mammals, a study relates the effect of Homeobox gene pattering to suggest that the reversal of the ancestral structural conditions are consistent with heterochrony in mammals. “Modern mammals have highly conserved pattern of vertebral indentites: seven cervical, 13 to 14 thoracic, and five or six lumbar vertebrae for a combined 19 or 20 thoracolumbar vertebrae. Homeobox genes pattern these regional vertebral identities. Homeotic changes in vertebral identities, such as shift of the thoracolumbar boundary or gradational transition, are now correlated with the loss and gain of hox genes function in mice. The distinctive boundary of thoracic versus lumbar regions and the absence of lumbar ribs are patterned by the Hox 10 paralogues in modern placental mammals. The triple knockout of Hox 10 paralogues can alter the thoracic versus lumbar boundary, and the triple knockout of Hox11 can alter lumbar versus sacral vertebral identities. Loss of hox 10 gene function an regenerated the lumbar ribs and a more gradational thoraco-lumbar transition in laboratory mice.” (Luo, Chen, Li, and Chen)
From a developmental perspective, specialists suggest that a trait classification system that integrates both functional and phylogenetic examinations of fossil mammals can determine whether selection acts on position or distribution, rather than individual features of adult morphology. “Targeted disruptions of Hox-11 in mice result in severe limb malformations, axial skeletal defects, and male infertility. However, deletion of one Hox D-11 transcriptional enhancer leads simply to caudal transposition of the sacrum; the limbs and genitals remain unaffected. It is worthy of note that because enhancer activity is influenced by other nuclear factors, actual evolutionary changes in morphology may not require mutations in the enhancers themselves. Localized changes in gene expression can also be generated by modulating the distribution of factors such as retinoic acid in a developmental field.” (Lovejoy, Cohn, and White ). An important case of rapid dramatic and morphological change is the evolution of hominid pelvis that provides an ideal example of Hox gene function. “Two novel features of the hominid pelvis dramatically improved its function during upright running and walking. First, the entire pelvis is greatly reduced in supero-inferior height. Second, virtually all of its individual “elements” are broader than I quadrupedal primates. In addition, the iliac blade, which is virtually parallel with the coronal plane in quadrupeds, has been “twisted” into the sagittal plane. This transformed it's attached muscles into the novel role of abductors that can prevent the pelvis from dropping to the unsupported side during the single leg phase of bipedal walking and running.” (Lovejoy, Cohn, and White ).
Natural selection constrained the number of cervical vertebrae in humans was investigated in a recent experiment. In this experiment, their data showed that homeotic transformations could change the number of cervical vertebrae are common but are selected against. “Homeotic transformations were first described by Bateson (1894) and are transformations of the identity of one structure into that of another. A well known example is the tranformations of the antennae of insects into legs as a result of antennapedia mutations. Cervical ribs appear to be partial or complete homeotic transformations of the seventh cervical vertebrae into rib-bearing thoractic vertebrae, that is, a posteriorization of the identity. Fishel (1906) and Leboucq (1898) found that vertebrae with a cervical rib usually display more shape characteristics of thoracic vertebrae than the mere presence of a rib. In addition Fishel (1906) and Oostra (2005) conclude that in the majority of cases cervical ribs are not isolated events, but are accompanied by homeotic changes of several adjacent cervical and thoracic vertebrae. In agreement with their observation, we found that approximately one-quarter of cervical ribs appear to be accompanied by a homeotic shift of all thoracic vertebrae. In addition, a similar proportion of cervical ribs are unilateral, and these tend to be accompanied by a larger first thoractic rib on that side than on the contralateral side, indicating a partial homeotic change of the first thoractic vertbra into that of the more posterior second thoracic vertebra. Of the rudimentary first ribs, a least 20% appear to be associated with a homeotic shift of all thoracic vertebrae and of the first lumbar vertebra. The Hox genes appear to be essential mediators of the anterior-posterior patterning of the presomitic mesoderm of the cervico-thoracic region and hence, to be involved in homeotic changes of vertebral identity. The expression of Hox genes involved in this pattering is spatially and temporally collinear and highly conserved. Our data suggest that mutations with an effect on the conserved expression of these genes during the anterior-posterior patterning of the praxial mesoderm may be common, but are strongly selected against.” (Galis, Van Dooren, Feuth, Metz, and Witkam 2643-2654).
Two genes essential for the development and function of mammalian female reproductive organs are Hox genes A-11 and A-13. In an investigative study, it was predicted that the coding region of these Hox genes played an active role in developmental evolution, and then these genes should have experienced adaptive evolution at the origin of mammalian species. “The evolution of mammals is associated with radical changes in their reproductive biology, particularly the structure and function of the female reproductive organs. These changes include the evolution of the uterus, cervix, vagina, placenta, and specialized cell types associated with each of those structures. The results presented show that the related genes of the Hox A cluster, HoxA-11 and HoxA-13, were under strong directional selection in the stem lineages of therian and eutherian mammals. The known functions for these genes are body axis development, limb development, blood cell differentiation, female reproductive development and formation of umbilical arteries. Out of these, only the function in the mammalian female reproductive organs and umbilicus originated coincident with the inferred selective episode reported here. Thus, the adaptive changes in these Hox proteins were most probably caused by their recruitment into novel developmental and cell biological functions associated with the evolution of the placenta, the uterus, endometrial cells and the vagina in mammals. Although positive selection has been identified in many genes, only recently has positive selection been identified in transcription factor genes. To our knowledge, this is the first case in which a specific evolutionary change in development, has been demonstrated to be coincident with adaptive molecular evolution of developmental control genes” (Lynch, Roth, Takahashi, Dunn, and Nonaka 2201-2207).
In another study, the evolution of the cis-regulatory element prolactin was examined. The expression of prolactin is essential for pregnancy in mammals and is a regulatory target of the transcription factor HoxA-11. “Although protein-mediated evolution of developmental pathways is rarely excluded as a means of gene regulatory evolution, the contribution of protein change to the origin of novel gene regulatory networks is generally not considered to play a major role in evolution. The primary argument against protein-mediated evolution of gene regulatory networks is the negative pleiotropic effects of mutations that are ascribed to changes in protein-coding genes. For example, given the multiple functions of HoxA-11 in blood cell differentiation and development of the body axis, limbs, kidney, and male and female reproductive systems, it seems unlikely that a novel function could emerge in endometrial cells without simultaneously having deleterious effects in these other contexts. However, our data indicate that selection acted to maintain ancestral functions during the emergence of a novel function by recruiting amino acids sites that were previously under weak functional constraints and thus free to acquire novel functions. The identification of an episode of adaptive evolution in HoxA-11 coincident with the origin of a novel function demonstrates a clear link between adaptive protein evolution and the emergence of a novel function. This and other examples of functional divergence among transcription factors indicate that the evolution of proteins themselves actively contributes to the evolution of development.” (Lynch, Tanzer, Wang, Leung, and Gellersen).
Recently, HoxA-10 has become a promising candidate that regulates the events successful pregnancy. HoxA-10 is also expressed in the menstrual cycle, and regulates ovarian hormones and embryonic signals. In this review, the events of decidualization and embryo implantation that are regulated by HoxA-10 are summarized. “ The occurrence of HoxA-10 expression during the different phases of endometrial receptivity has been extensively characterized in different species including primates, and mouse genetic models have provided unequivocal proof that this gene is required for implantation and decidualization. While several HoxA-10 target genes have been identified using the null mutant mouse uteri, unfortunately this list is still very short and contains genes not conclusively shown to be direct targets. Nevertheless, global gene profiling analysis of uterine cells where HoxA-10 has been perturbed has suggested that this gene is a potent regulator of cellular proliferation in the endometrium. In addition, the data also suggest that HoxA-10 may transform the local immunological milieu in the uterus making it conducive for implantation and maintenance of pregnancy. To more fully understand the role of HoxA-10, future research needs to focus on identifying and characterizing more direct gene targets. Expanding knowledge of target gene that are directly regulated by Hox proteins would delineate the pathways by which Hox genes enable responsiveness of the endometrium to several external regulatory signals such as ovarian hormones and the embryo.” (Modi, and Godbole 72-78).
Homeobox genes or Hox genes are responsible for proper body axis development, and is greatly significant in evolving mammalian species. Hox genes are one of many factors that provide a change that is considered a means for genetic evolution. Hox genes commonly regulate limb or wing segmentation in mice and fruit flies. Hox genes can also regulate mammalian female hormones during pregnancy. While different scientists of accredited disciplines form there own hypothesizes regarding the function of Hox genes, many possess similar knowledge of these genes with their own methods.
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