Fundamentals | Genetics | Achievable USMLE/1

A gene is the basic physical and functional unit of heredity. Humans have between 20,000 and 25,000 genes, which vary in size from a few hundred DNA bases to more than 2 million bases per gene. Genes are made up of DNA. They code for proteins. There are genes called non-coding genes that do not code for proteins. Majority of DNA does not code for proteins but instead act as regulatory elements like promoters, enhancers, repressors etc. or structural elements like telomeres, satellite DNA, introns etc. Every individual has two copies of each gene, one copy is inherited from the father and one from the mother. Alleles are forms of the same gene with small differences in their sequence of DNA bases. DNA is packed into thread-like structures called chromosomes. Each chromosome is made up of DNA tightly coiled many times around proteins called histones. Each cell contains 23 pairs i.e. total 46 chromosomes. Of 23 pairs, 22 pairs are autosomes while 1 pair is of sex chromosomes, which will be XX in females and XY in males.

Common definitions used in genetics:

Alleles: Variants of a given DNA sequence at a particular locus in the genome or variants of the same gene. For example, there are different alleles for eye color - black, brown , blue etc.
Allelic heterogeneity: Different mutations in the same gene that cause different phenotypic manifestations or severity of disease. For example, androgen insensitivity can present as more or less severe forms depending on the type of mutation and how much functional loss occurs as a result of that.
Non Allelic or locus heterogeneity: The same phenotype is caused by mutations in genes at different chromosomal loci. For example, nephrogenic diabetes insipidus may be caused by mutations in either aquaporin 2 gene or AVPR2 gene.

Genetic heterogeneity is a result of allelic and locus heterogeneity.
Homozygote: When both alleles at a particular gene locus are the same. A person may be homozygous for the normal allele or for a mutation.
Heterozygote: When the two alleles at a particular gene locus are different. A heterozygous genotype may include one normal allele and one mutation, or two different mutations. The latter is called a compound heterozygote.
Hemizygous: Having only one copy of a gene or DNA sequence in diploid cells. Males are hemizygous for most genes on sex chromosomes, having only one X and one Y chromosome. A person having a deletion in a region of an autosome would be hemizygous for that region, having one remaining copy on the normal homologous chromosome
Dominant: Any trait that is expressed in a heterozygote.
Dominant negative: A mutant gene whose product can inhibit the function of the wild-type gene product in heterozygotes
Haploinsufficiency: When one copy of a gene is inactivated or deleted and the remaining functional copy of the gene is not adequate to produce the needed gene product to preserve normal function. It will clinically manifest as a dominant trait.
Haplotype: A set of closely linked genetic markers present on one chromosome which tend to be inherited together
Genotype: The set of alleles that make up an individual’s genetic make-up either overall, or at a given locus
Phenotype: The observable characteristics in an individual resulting from the expression of genes; the clinical presentation of an individual with a particular genotype.
Proband: The individual through whom a family with a genetic disorder is ascertained. In males this is called a propositus, and in females it is called a proposita.
Incomplete penetrance: When an individual carries the pathogenic genotype but does not phenotypically manifest the disease e.g. amongst individuals with inherited BRCA gene mutations some may develop cancers while others do not.
Variable expressivity: It refers to the range of signs and symptoms that can occur in different people with the same genetic condition. Those carrying the defective gene will express the disease, but in milder to more severe forms e.g. in Marfan’s syndrome some will be tall and have long fingers but no cardiovascular involvement while others may have aortic dissection.
Mosaicism: The occurrence of 2 or more cell lines with different genetic or chromosomal make-up, within a single individual or tissue.