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doi: 10.1002/bies.950181204pmid: 8976151
The common ancestor of modern humans and the great apes is estimated to have lived between 5 and 8 Myrs ago, but the earliest evidence in the human, or hominid, fossil record is Ardipithecus ramidus, from a 4.5 Myr Ethiopian site. This genus was succeeded by Australopithecus, within which four species are presently recognised. All combine a relatively primitive postcranial skeleton, a dentition with expanded chewing teeth and a small brain. The most primitive species in our own genus, Homo habilis and Homo rudolfensis, are little advanced over the australopithecines and with hindsight their inclusion in Homo may not be appropriate. The first species to share a substantial number of features with later Homo is Homo ergaster, or ‘early African Homo erectus’, which appears in the fossil record around 2.0 Myr. Outside Africa, fossil hominids appear as Homo erectus‐like hominids, in mainland Asia and in Indonesia close to 2 Myr ago; the earliest good evidence of ‘archaic Homo’ in Europe is dated at between 600–700 Kyr before the present. Anatomically modern human, or Homo sapiens, fossils are seen first in the fossil record in Africa around 150 Kyr ago. Taken together with molecular evidence on the extent of DNA variation, this suggests that the transition from ‘archiac’ to ‘modern’ Homo may have taken place in Africa.
Schafer, Alan J.; Goodfellow, Peter N.
doi: 10.1002/bies.950181205pmid: 8976152
In mammals, the Y chromosome induces testis formation and thus male sexual development; in the absence of a Y chromosome, gonads differentiate into ovaries and female development ensues. Molecular genetic studies have identified the Y‐located testis determining gene SRY as well as autosomal and X‐linked genes necessary for gonadal development. The phenotypes resulting from mutation of these genes, together with their patterns of expression, provide the basis for establishing a hierachy of genes and their interactions in the mammalian sex determination pathway.
doi: 10.1002/bies.950181206pmid: 8976153
About one in forty babies is born with a recognisable congenital anomaly at birth. Rapid progress is being made in recognising the genetic contribution to these defects. From over 2000 likely single gene malformation syndromes in humans the gene has been isolated or mapped in about 10%. Despite the availability of animal models, the study of malformations in humans continues to reveal novel genes and unpredicted functions for known genes. The importance of the study of clinical malformations to the understanding of embryological development in humans and other organisms is discussed and reviewed.
Gerhold, David; Caskey, C. Thomas
doi: 10.1002/bies.950181207pmid: 8976154
ESTs or ‘expressed sequence tags’ are DNA sequences read from both ends of expressed gene fragments. The Merck‐WashU EST Project and several other public EST projects are being performed to rapidly discover the complement of human genes, and make them easily accessible. These ESTs are widely used to discover novel members of gene families, to map genes to chromosomes as ‘sequence‐tagged sites’ (STSs), and to identify mutations leading to heritable diseases. Informatic strategies for querying the EST databases are discussed, as well as the strengths and weaknesses of the EST data. There is a compelling need to build on the informatic synthesis of human gene data, and to devise facile methods for determining gene functions.
Grossman, Lawrence I.; Shoubridge, Eric A.
doi: 10.1002/bies.950181208pmid: 8976155
Mitochondria contain a molecular genetic system to express the 13 protein components of the electron transport system encoded in the mitochondrial genome (mtDNA). Defects in the function of this system result in some diaseases, many of which are multisystem disorders, prominently involving highly aerobic, postmitotic tissues. These defects can be caused by large‐scale rearrangements of mtDNA, by point mutations, or by nuclear gene mutations resulting in abnormalities in mtDNA. Although any of these mutations would be expected to produce a similar clinical phenotype by compromising oxidative phosphorylation, the surprising and puzzling result is that different clinical phenotypes are generally associated with specific mtDNA mutations. Moreover, the same mutation can produce a distinct clinical phenotype in different individuals or pedigrees. MtDNA rearrangements are also found in aged individuals, but at a subclinical level, suggesting that normal and pathological processes can differ by the effect of genetic or environmental factors on the error rate of mtDNA replication.
doi: 10.1002/bies.950181209pmid: 8976156
There has always been great interest in animal models of human genetic disease, and mice provide the largest number of examples. A mutation in the homologous gene in mice does not always lead to the same phenotype as is found in man, however. Recent studies made it apparent that one mutation can have markedly different phenotypes when placed on different genetic backgrounds. This variation is due to different alleles at modifying loci in various inbred strains. Thus, if one wishes to obtain the optimal mouse model for a human disease, one needs to choose the correct genetic background as well as the correct mutation.
doi: 10.1002/bies.950181210pmid: 8976157
The prelude to successful human somatic gene therapy, i.e. the efficient transfer and expression of a variety of human genes into target cells, has already been accomplished in several systems. Safe methods have been devised to do this using non‐viral and viral vectors. Potentially therapeutic genes have been transferred into many accessible cell types, including hematopoietic cells, hepatocytes and cancer cells, in several different approaches to ex vivo gene therapy. Successful in vivo gene therapy requires improvements in tissuetargeting and new vector design, which are already being sought. Gene‐transfer protocols have been approved for human use in inherited diseases, cancer and acquired disorders. Althouth the results of these trials to date have been somewhat disappointing, human somatic cell gene therapy promises to be an effective addition to the arsenal of approaches to the therapy of many human diseases in the 21st century if not sooner.
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