Dna And Human Diversity

Though individuals can differ greatly in appearance and risk for disease, they are surprisingly alike at the genetic level, sharing approximately 99.9 percent of their genomes in common. This statistic is somewhat misleading in that the approximate 0.1 percent difference is comprised of as many as four million mutations and variations spanning approximately 12 million base pairs.1 As opposed to mutations which occur in individuals or even

Gene

DNA

Exon 1

Intron 1

Exon 2

Intron 2

Exon S

Transcription (RNA synthesis)

Exon 1

Intron 1

Exon 2

Intron 2

Nuclear RNA

Messenger RNA

Translation > r (Protein synthesis)

Protein

Figure 4.3 Transcription unit of a gene. The transcription unit of a gene has nucleotides providing information other than the nucleotide triplicates (codon) that code for amino acids. The promoter area is involved with regulation of the rate and tissue distribution of transcription. The initiator site and the initiation codon indicate where transcription and translation begins, respectively. The termination site and stop codon indicates where transcription and translation stops, respectively. Genes often have areas that are not included in the final mRNA (introns); exons are spliced together to form the mRNA, which is then translated into a protein. Reprinted from National Institute of General Medical Sciences. The New Genetics. Bethesda, MD, USA: National Institute of General Medical Sciences, 2006: 15. Available from: http:// publications.nigms.nih.gov/thenewgenetics/ index.html.

Second letter

U

C

A

G

UUU

Phe

UCU

UAU

Tyr

UGU

Cys

U

U

UUC

UCC

Ser

UAC

UGC

C

UUA

Leu

UCA

UAA

Ochre*

UGA

Opal #

A

UUG

UCG

UAG

Amber*

UGG

Trp

G

CUU

CCU

CAU

His

CGU

U

C

CUC

Leu

CCC

Pro

CAC

CGC

Arg

C

CUA

CCA

CAA

Gln

CGA

A

CUG

CCG

CAG

CGG

G

AUU

ACU

AAU

Asn

AGU

Ser

U

A

AUC

Ileu

ACC

Thr

AAC

AGC

C

AUA

ACA

AAA

Lys

AGA

Arg

A

AUG

Met*

ACG

AAG

AGG

G

ter

GUU

GCU

GAU

Asp

GGU

U

CD

G

GUC

Val

GCC

Ala

GAC

GGC

Gly

C

GUA

GCA

GAA

Glu

GGA

A

"D

¡JL

GUG

GCG

GAG

GGG

G

JZ 1-

a family, sequence variations occur at frequencies ranging from 1 to 50 percent in the general population. These variations have the potential to influence many aspects of biology, health, and disease. The majority of these variations do not occur within the coding regions of the estimated 20,000 to 25,000 genes in the human genome. However, the remaining subset of variations that do occur in gene regions result in different alleles that provides a rich tool for human genetic investigation.

Figure 4.4 Each codon in messenger RNA specifies the initiation signal, amino acid or termination signal called for in a given polypetide chain, or protein. * Initiation codon, # termination codons. Amino acid three-letter and single-letter abbreviations: alanine, Ala(A); arginine, Arg(R); aspartic acid, Asn(N); asparagine, Asx(B); cysteine, Cys(C); glutamine, Gln(Q); glutamic acid, Glu(E); glutamine, Glx(Z); glycine, Gly(G); histidine, His(H); isoluecine, Iso(I); leucine, Leu(L); lysine, Lys(K); methionine, Met(M); phenylalanine, Phe(F); proline, Pro(P); serine, Ser(S); threonine, Thr(T); tryptophan, Trp(W); tyrosine, Tyr(Y); valine, Val(V).

Genetic variations, also referred to as polymorphisms, occur in many forms and include: single nucleotide polymorphisms (SNPs), small-scale insertions/deletions, and repetitive elements (e.g. satellite DNA). Satellite DNA is common throughout the genome. These groups of variations are segments of DNA which are repeated in tandem and result in many alleles in the population. Historically, these satellite DNA have proven quite useful in the mapping of disease-causing genes in the human genome2,3 and to differentiate individuals (e.g. paternity testing4). By far the most common variations are SNPs. Polymorphisms (e.g. SNPs) can change a gene's transcript or protein product, alter a gene's temporal or spatial expression, or silence its expression altogether.

The impact of a mutation or a polymorphism on the phenotype of an individual depends on many factors. Phenotype refers to a characteristic or trait of an individual that is observable or measurable. One's genetic constitution, or genotype, is a major determinant of phenotype. For example, an individual heterozygous for a deleterious allele is likely to display an intermediate phenotype in comparison to an individual homozygous for this deleterious allele. Another factor that impacts a phenotype is whether an allele exerts a dominant, a recessive, or an additive influence. In the case of autosomal dominant inheritance, it takes only one mutated allele to express a trait. In the case of autosomal recessive inheritance, only an individual homozygous for the recessive allele will express the trait. Whether a trait is dominant or recessive in its inheritance depends in part on whether the functional effect of the mutation or variation can be compensated for by other factors. In the case of additive inheritance, each additional allele contributes incrementally to a trait.

A pedigree diagram is often used to visually represent the genetic history of a family for a given disease or trait (Figure 4.5). Pedigree charts are used to determine patterns of inheritance, as well as the risk that a specific individual will develop a trait or disease. Dominant and recessive patterns of inheritance can occur with the sex chromosomes and are termed X-linked or Y-linked dominant or recessive. Examples of autosomal dominant, autosomal recessive, and X-linked recessive inheritance are illustrated in Figure 4.5a, 4.5b, and 4.5c, respectively. A less common pattern of inheritance is mitochondrial inheritance. Transmission is maternal and thus affected men do not pass on the trait.

A subset of individuals that carry a specific disease-causing genotype do not display the trait or disease because the disease or even the specific allele displays incomplete penetrance. Of note, a certain degree of penetrance is explained in part by the sensitivity of the measure of a phenotype. Variations in penetrance and phenotypic expression of a gene may be related to gene -gene interactions (i.e. one gene modulates the expression of another) or environment-gene interactions (i.e. environmental factors modulate the expression of a gene).

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