Molecular biology of genes controlling neural specificity

In molecular terms, a gene commonly is defined as the entire nucleic acid sequence that is necessary for the synthesis of a functional polypeptide.

Molecular biology of genes controlling neural specificity

Author: Hafiza Syeda Haya Naz

According to this definition, a gene includes more than the nucleotides encoding the amino acid sequence of a protein, referred to as the coding region. A gene also includes all the DNA sequences required for synthesis of a particular RNA transcript.

Although most genes are transcribed into mRNAs, which encode proteins, clearly some DNA sequences are transcribed into RNAs that do not encode proteins (e.g., tRNAs and rRNAs).

However, because the DNA that encodes tRNAs and rRNAs can cause specific phenotypes when they are mutated, these DNA regions generally are referred to as tRNA and rRNA genes, even though the final products of these genes are RNA molecules and not proteins. Many other RNA molecules described in later chapters also are transcribed from non-protein-coding genes.

Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA (rRNA) genes or transfer RNA (tRNA) genes, the product is a functional RNA.

The process of gene expression is used by all known life – eukaryotes (including multicellular organisms), prokaryotes (bacteria and archaea) and viruses – to generate the macromolecular machinery for life.

Several steps in the gene expression process may be modulated, including the transcription, RNA splicing, translation, and post-translational modification of a protein.

Gene regulation gives the cell control over structure and function, and is the basis for cellular differentiation, morphogenesis and the versatility and adaptability of any organism. A molecule which allows the genetic material to be realized as a protein was first hypothesized by François Jacob and Jacques Monod. 

Proteins form the internal machinery within brain cells and the connective tissue between brain cells. They also control the chemical reactions that allow brain cells to communicate with each other.

Some genes make proteins that are important for the early development and growth of the infant brain. For example, the ASPM gene makes a protein that is needed for producing new nerve cells (or neurons) in the developing brain. Alterations in this gene can cause microcephaly, a condition in which the brain fails to grow to its normal size.

Certain genes make proteins that in turn make neurotransmitters, which are chemicals that transmit information from one neuron to the next. Other proteins are important for establishing physical connections that link various neurons together in networks.

Still other genes make proteins that act as housekeepers in the brain, keeping neurons and their networks in good working order.

For example, the SOD1 gene makes a protein that fights DNA damage in neurons. Alterations in this gene are one cause of the disease amyotrophic lateral sclerosis (ALS), in which a progressive loss of muscle-controlling neurons leads to eventual paralysis and death. The SOD1 gene is believed to hold important clues about why neurons die in the common “sporadic” form of ALS, which has no known cause.

Most of the single gene mutations that cause rare neurological molecular disorders such as Huntington’s disease have been identified. In contrast, there is still much to learn about the role of genetic variations in common neurological disorders and conditions, like Alzheimer’s disease and stroke. A few things are clear.

First, for most people, a complex interplay between molecular genes and environment influences the risk of developing these diseases. Second, where specific genetic variations such as SNPs are known to affect disease risk, the impact of any single variation is usually very small.

In other words, most people affected by stroke or Alzheimer’s disease have experienced an unfortunate combination of many “hits” in the genome and in the environment. Finally, beyond changes in the DNA sequence, changes in gene regulation – for example, by sRNAs and epigenetic factors – can play a key role in disease.

Scientists search for connections between genes and disease risk by performing two kinds of studies. In a genome-wide association (GWA) study, scientists search for SNPs or other changes in the DNA sequence, comparing the genomes of subjects (people, laboratory animals or cells) that have a disease and subjects that do not have the disease.

In another type of study called gene expression profiling, scientists look for changes in gene expression and regulation that are associated with a disease.

Both kinds of molecular studies often use a device called a DNA microarray, which is a small chip, sometimes called a gene chip, coated with row upon row of DNA fragments. The fragments act as probes for DNA (in a GWA study) or RNA (in gene expression profiling) isolated from a sample of blood or tissue.

Increasingly, scientists are conducting these molecular studies by direct sequencing, which involves reading DNA or RNA sequences nucleotide by nucleotide. Sequencing was once a time-consuming and expensive procedure, but a new set of techniques called next-generation sequencing has emerged as an efficient, cost-effective way to get a detailed readout of the genome.