Catálogo de publicaciones - libros

I came to Houston, Texas in 1986 with one goal being to identify “the gene” for Charcot-Marie-Tooth (CMT) disease. I was peripherally aware of the paper by Botstein and colleagues () proposing the genetic mapping of human “disease genes” using linked restriction fragment length polymorphisms (RFLPs) to position the gene within the human genome and indeed became very excited as a graduate student when Gusella’ s paper () appeared in Nature linking the Huntington disease locus to markers on chromosome 4. It was a natural extension to think this “positional cloning“ approach might be applied to a host of other human traits. There was apersonal, one might say egocentric, reason to choose CMT because I have the disease () and, in fact, the first blood samples collected for DNA linkage studies were from my own family wherein CMT segregated as an apparent autosomal recessive trait.

elements represent one of the most successful mobile elements found in any genome. They have reached a copy number in excess of one million copies, making up more than 10% of the human genome. The level of amplification required to reach this high copy number has created an enormous number of insertion mutations resulting in human disease and genome evolution. They also add extensive diversity to the genome by introducing alternative splicing and editing to a wide range of RNA transcripts. In addition, after insertion elements contribute to a high level of genetic instability through recombination. This instability contributes to a significant number of germ-line mutations and may be an even bigger factor in cancer and/or aging.

Long interspersed element-1 (LINE-1 or L1) is an abundant retrotransposon that comprises approx 17% of human DNA. L1 retrotransposition events can lead to genome diversification and individual genetic variation by serving as insertional mutagens and by providing recombination substrates either during or long after their insertion. L1 retrotransposition also generates genomic variation by mobilizing DNA derived from its flanks, non-autonomous retrotransposons (e.g., Alu elements), and cellular mRNAs to new genomic locations. Together, these sequences comprise approx 15% of human genomic DNA. Thus, L1-mediated retrotransposition events are responsible for at least one-third of our genome. In this chapter, we discuss how innovative assays developed in recent years have increased our understanding of L1 biology and the impact of L1 on the human genome.

The human genome contains a large number of repetitive elements derived from transposable elements (TEs). In addition to active Alu and long interspersed element (LINE or L1) interspersed repeats, the human genome comprises a large number of ancient TEs. These include fossil germ-line insertions of DNA transposons, fossil short interspersed elements (SINEs), L2, and L3 LINEs. Processed pseudogenes and human endogenous retroviruses (HERVs) have amplified more recently in evolutionary history and some of them are still well preserved. Copies of some of the recently extinct TEs continue to contribute to genomic rearrangements by homologous recombination. In this chapter, we review ancient SINE and LINE repeats, processed pseudogenes, HERVs, and DNA transposons. We briefly introduce the genomic structure and replication strategy of these elements, their expression competence, and focus on the contribution of these repeats to human diseases. We also discuss some of the TE-derived genes and regulatory elements.

Until recent times, the identification and characterization of segmental duplications has often been based purely on anecdotal reports. However, the completion of the Human Genome Project has now made possible the systematic analysis of the extent and distribution of duplicated sequences in humans. Both in situ hybridization and in silico approaches have shown that approx 5% of our genome is composed of highly homologous duplicated sequence (,), with enrichments of six- to sevenfold in pericentromeric (), and two- to threefold in subtelomeric regions (), respectively. Not only does the presence of these paralogous segments represent a significant challenge to the correct assembly of the human genome, but there is also an increasing awareness of their role in human evolution, variation, and disease. We present a review of segmental duplications in the mammalian genome. We describe their basic characteristics, distribution, and dynamic nature during recent evolutionary history. Based on these features, we discuss models to account for the proliferation of these sequences in the mammalian lineage, and also their contribution towards karyotypic evolution and phe-notypic differences between primates. Finally, we highlight the role of segmental duplications as mediators of human variation at the genomic level.

Certain DNA sequences in the genome may exist either in the canonical right-handed B-duplex or in alternative non-B conformations, depending on conditions such as transcription, supercoil stress, protein binding, and so on. Analyses of breakpoint junctions at deletions, translocations, and inversions, where the sites of DNA breakage could be determined at the nucleotide level, revealed that most, if not all, of the breaks occurred within, or adjacent to, the predicted non-B conformations. These findings support a model whereby rearrangements are caused by recombination/repair processes between two distinct non-B conformations, which may reside either on the same chromosome or on two distinct chromosomes. This model was applicable to both Escherichia coli and humans, suggesting that the mechanisms involved are highly conserved.

The completion of the human genome sequencing has opened new opportunities to better understand complex biological systems. In this realm, the human sense of smell is an excellent example of how genome analysis provides new information on genome organization and on deficits. Before the advent of genomic tools, the understanding of this highly sophisticated sensory neuronal pathway has been rather sketchy. In this chapter we summarize the relevant progress made in the last decade, and highlight the initial elucidation of two classes of olfactory deficits and their possible underlying genetic mechanisms.

Centromeres are required for normal chromosome segregation in mitosis and meiosis, and a substantial proportion of human pathology stems from abnormalities of chromosome segregation, the underlying genomic basis and mechanism(s) of which are largely unknown. Human centromeres consist of megabases ofα-satelliteDNA, atandemlyrepeatedDNA family whose genomic organization, evolution, and function is increasingly well understood. The study of normal, abnormal, and engineered human chromosomes is providing insights into the nature of human centromeres and their mechanism of action, as well as enabling comparison with centromeres of other eukaryotic organisms and the identification of genomic elements required for normal centromere function.

During the last two decades, comparative cytogenetics and genomics has evolved from a specialized discipline to a highly dynamic field of research. This development was driven by major technological advancements as well as emergence of the deeper insight that many aspects of human genome function can be better understood when information about its evolutionary changes is taken into account. Whole-genome sequencing projects of biomedical model species and domesticated animals provided important clues to the molecular mechanisms that shaped the human genome. These strategies were complemented by the launch of the chimpanzee genome project, leading to the recent publication of the first chimpanzee draft sequence and its alignment with the human reference sequence.

The centromere repositioning phenomenon consists in the move of the centromere along the chromosome during evolution. This phenomenon is relatively frequent, and has been documented in primates, nonprimate mammals, and birds. It implies the inactivation of the old centromere and the rapid progression of the newly seeded centromere toward the complex organization that probably stabilizes its activity. Both events have a huge impact on chromosomal architecture. The segmental duplicon clusters at 6p22.1 and 15q24-26 are clear examples of remains of inactivated ancestral centromeres. These duplicons are dispersed in a relatively large area (approx 10 Mb), and contribute to the bulk of nonpericentromeric segmental duplications that constitute approx 5% of the human genome.