Biology Of Molecular Genetics

Biological effects are primarily initiated from genomic DNA and mediated through expression of gene products, either RNA or protein. Genes are composed of exons (protein-coding regions), introns (noncoding regions spliced out of the mRNA), and regulatory regions. Gene discovery has progressed with the sequencing of large numbers of expressed sequences (ESTs) representing mRNAs of genes. Trait differences are inherited due to variation or mutation of the parent DNA molecule, and these effects are transmitted to the RNA transcripts that code for mature proteins. Nucleotide variations that can affect expression include single nucleotide polymorphisms (SNPs; previously identified as restriction fragment length polymorphisms, or RFLPs), small insertions or deletions (indels), or variation that encompasses larger portions of genomic DNA. Variation in an RNA transcript can affect the protein code directly as a change in the coding template or a change in efficiency of initiation, transcription, stability of the message, or correct splicing of exonic sequences that code for the translated protein. Changes in the protein's amino acid sequence can affect protein function, folding, or posttranslational modifications. Sequence variation in regulatory regions of genes containing promoters, enhancers, or repressors (very short transcription factor-binding sites) can alter timing, location, or levels of expression. Inheritance of variation can be manifested as measurable traits, biochemical deficiencies, or developmental abnormalities. Mode of inheritance is usually crucial to understanding the molecular genetics of a particular phenotype, i.e., whether the trait is inherited as a recessive, dominant, additive, or sex-linked trait. Deficiencies are usually easiest to study because we can rely on knowledge of biochemistry to determine defects in metabolic pathways. Developmental defects are more difficult to study because phenotype may be determined during very short and specific stages during development. Quantitative traits are assumed to be under the control of many genes and require specific approaches to detect genomic regions that contribute to an overall phenotype. Linkage analysis is one common approach used to guide the molecular genetic study of inherited traits by identifying positional candidate genes.

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