ABSTRACT

Supratim Choudhuri U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition , OFAS, Division of Biotechnology and GRAS Notice Review , College Park , Maryland , U.S.A.

1. INTRODUCTION-THE SCOPE OF GENOMICS 51 1.1. Genome Mapping 51 1.1.1. Genetic Maps of the Genome 52 1.1.1.1. Principles of genetic mapping were established by

research in Drosophila genetics in the early part of the twentieth century 52

1.1.1.2. Genetic mapping in humans 52 1.1.2. Physical Maps of the Genome 53 1.1.2.1. Cytogenetic maps 53 1.1.2.2. Radiation hybrid maps 53 1.1.2.3. Sequence maps 54 2. NUCLEOPROTEIN ORGANIZATION OF THE GENOME 55 2.1. Chromatin-the DNA-Protein Complex that Stabilizes the Genome

and Regulates its Expression 55 2.1.1. Nucleosome (Chromatin) Assembly 55 2.1.2. Histone Variants, Deviant Nucleosomes, and Specialized Functions 57 2.1.3. NonHistone Proteins in the Chromatin-the HMG Proteins 59 2.1.4. Chromatin Modifi cation 59 2.1.5. Chromatin Remodeling Complex 59 2.2. Heterochromatin and Euchromatin 60 2.2.1. Heterochromatin-Associated Proteins 61 2.2.2. Heterochromatin Spread and Position Effect Variegation 62 2.3. Nuclear Matrix, Matrix Attachment Regions, and Chromatin Loops 62 3. GENOMIC DNA AS A MOSAIC OF ISOCHORES 63 3.1. Different Families of Isochores and Their Properties-GC-Content,

Gene Distribution, and Codon Usage Bias 64 3.2. In Search of the “Iso” in Isochores 65

4. GENOMIC LANDSCAPE AS REVEALED BY GENOME SEQUENCING 67 4.1. Human Genome 67 4.1.1. The Protein-Coding Landscape 67 4.1.2. Gene Birth and Death in Human Lineage 68 4.1.3. Genomic GC-Content 69 4.1.4. CpG Islands 69 4.1.5. Recombination Rate 70 4.1.6. Repeat Content 70 4.1.6.1. C-value, C-value paradox, and C0t analysis 70 4.1.6.2. Types of repeat sequences in the human genome 71 4.1.6.2.1. Interspersed (transposon-derived) repeats 72 4.1.6.2.2. Processed psuedogenes 75 4.1.6.2.3. Simple sequence repeats 76 4.1.6.2.4. Segmental duplications 76 4.1.6.2.5. Tandem repeat blocks 77 4.1.7. Noncoding RNA (ncRNA) Genes 78 4.1.8. Human Proteome Analysis 79 4.1.9. Duplications in the Human Genome and Composite Structure

of Human Proteins 79 4.1.10. Genome-Wide Chromatin Marks and Transcription 80 4.1.10.1. Pervasive transcription in the human genome 80 4.1.10.2. Antisense transcription 82 4.1.11. Human Genomic Variations 82 4.1.11.1. Single nucleotide polymorphism 83 4.1.11.2. Copy number variation 83 4.2. The Chimpanzee Genome 84 4.2.1. Similarity in Protein-Coding Genes Between Human

and Chimpanzee 84 4.2.1.1. Evolution of the coding sequences 85 4.2.1.2. Gene expression 85 4.2.2. Possible Causes of Genome-Wide Nucleotide Divergence Between

Human and Chimpanzee 86 4.2.2.1. Divergence in CpG islands 86 4.2.2.2. Divergence due to indel mutations 86 4.2.2.3. Divergence due to transposable elements 86 4.2.2.4. Divergence due to deletions, repeat sequences, and

chromosomal rearrangements 87 4.2.2.5. Single nucleotide polymorphisms 87 4.2.3. Positive Selection and Genome Evolution 87 4.2.3.1. Neutral theory of molecular evolution 88 4.2.3.2. Signatures of positive selection in the genome 88 4.2.3.3. Genome evolution in human and chimpanzee 90 4.2.3.3.1. Molecular evolution of FOXP2 gene 90 4.2.3.3.2. Molecular evolution of genes regulating brain size 91 4.2.3.3.3. Molecular evolution of MYH16 gene 92 4.2.3.3.4. Molecular evolution of CMAH gene 92 4.3. Rhesus Macaque Genome 92 4.4. Mouse Genome 93 5. CHROMOSOMAL SYNTENY AND SYNTENIC MAPS

IN COMPARATIVE GENOMICS 94

1. INTRODUCTION-THE SCOPE OF GENOMICS The goal of the science of genomics is to study the structure, function, and evolution of the genome. An extension of this goal is to understand how environmental factors modulate genome function. This has direct relevance to clinical genomics.