Genetics Chapter 1 & 2 - Introduction to Human Genome

Introduction to Human Genome Chapter 1, 2, and 5 The Human Genome and the Chromosomal Basis of Heredity The human genome consists of large amounts of the chemical deoxyribonucleic acid (DNA) that contains within its structure the genetic information to keep the organisms functional. Every nucleated...

Introduction to Human Genome Chapter 1, 2, and 5 The Human Genome and the Chromosomal Basis of Heredity The human genome consists of large amounts of the chemical deoxyribonucleic acid (DNA) that contains within its structure the genetic information to keep the organisms functional. Every nucleated cell in the body carries its own copy of the human genome, which contains ~ 20,000 to 50,000 genes. Genes are organized into a number of rod-shaped organelles called chromosomes in the nucleus of each cell. Chromosome and genome analysis has become important diagnostic procedures in clinical medicine Human chromosomes  Human somatic cells are diploid and have 22 pairs of chromosomes (paternal and maternal) and 1 set of sex chromosome (XX or XY).  Germ cells are haploid and contain 22 chromosomes and 1 sex chromosome (X or Y). Structure of Human Chromosomes Each chromosome is one long, double-stranded DNA molecule, and the nuclear genome consists therefore of 46 linear DNA molecules, totaling more than 6 billion nucleotide pairs The Human Karyotype Karyogram: An ordered arrangement of the chromosomes from a cell placed in a standard sequence (from longer to shorter) The Human Genome Sequence - The genome map determined the sequence of the 3.3 billion bp of DNA located among the 24 types of human chromosomes. - Consensus (or canonical) sequence In genes or proteins, a sequence in which each base or amino acid residue represents the one most frequently found at that position. Organization of the Human Genome Of the billions of base pairs of DNA in any genome, fewer than 1.5% actually encodes proteins. This portion of the genome is referred to as the exome (the sequence of all the exons in a genome). Organization of the Human Genome - Single copy DNA sequences - Repetitive DNA sequences Tandem repeats/ Satellite DNAs: Satellite DNA consists of very large arrays of tandemly repeating, non-coding DNA. Satellite DNA is the main component of functional centromeres and form the main structural constituent of heterochromatin. The Human Karyotype Transmission of the Genome/ The Cell Cycle Transmission of the Genome Mitosis (Somatic cells) results in diploid cells. Meiosis (Germline cells) results in haploid cells. Mitosis Meiosis  Meiosis I is also known as the reduction division because it is the division in which the chromosome number is reduced by half through the pairing of homologues in prophase and by their segregation to different cells at anaphase of meiosis I.  Crossing over (genetic recombination) occurs in Meiosis I. Meiosis Meiosis Leptotene: Replicated chromosomes align and start to condense. Zygotene: Homologous chromosomes synapsis. The paired homologues (bivalents) are held together by a ribbonlike proteinaceous structure called the synaptonemal complex. Pachytene: Synapsis completes and crossing over occurs (chiasmata). Diplotene: Homologous chromosomes separate but still bound at chiasmata. Diakinesis: Dissolution of nuclear membrane. The genetic content of each gamete is unique because of random assortment of the parental chromosomes and homologous recombination. The amounts and patterns of meiotic recombination are determined by sequence variants in specific genes and at specific “hot spots” and differ between individuals, sexes, families, and populations. Failure of proper homologues chromosomes recombination can lead to chromosome missegregation (nondisjunction) in meiosis I and is a frequent cause of pregnancy loss and of chromosome abnormalities such as Down syndrome. Although homologous recombination is a normal and essential part of meiosis, it also occurs, albeit more rarely, in somatic cells. Anomalies in somatic recombination are one of the causes of genome instability in cancer Abnormalities of Chromosome Structure Structural rearrangements result from chromosome breakage, recombination, or exchange, leading to an abnormal combination of genetic material. They can be present in all cells of a person or in mosaic form. Structural rearrangements are classified as balanced if the genome retains the normal complement of chromosomal material or unbalanced if material is additional or missing. Some rearrangements are stable and can pass through cell divisions unaltered, while others are unstable. Abnormalities of Chromosome Structure Unbalanced rearrangements It occurs in approximately 1 in 1600 live births and often result in abnormal phenotypes due to the deletion or duplication of multiple genes, or both. Duplication of a chromosome segment leads to partial trisomy for the genes within that segment, while deletion results in partial monosomy. Disturbance of normal gene dosage balance can lead to abnormal development, with a wide range of phenotypes depending on the specific genes affected. Abnormalities of Chromosome Structure Deletions Autosomal deletions visible through cytogenetic analysis occur in about 1 in 7000 live births. Deletions involve the loss of a chromosome segment, causing a chromosome imbalance. Carriers of chromosomal deletions are monosomic for the genetic information on the corresponding segment of the normal homologue. Clinical consequences typically reflect haploinsufficiency, where a single copy of genetic material cannot perform the functions normally carried out by two copies. Abnormalities of Chromosome Structure Deletions The severity of consequences depends on the size of the deleted segment and the number and function of the specific genes affected. Deletions can occur at the end of a chromosome (terminal) or within a chromosome arm (interstitial), possibly originating from chromosome breakage and loss of the acentric segment. Abnormalities of Chromosome Structure Duplications Duplication is generally considered less harmful than deletion, but it can lead to chromosomal imbalance (partial trisomy) in gametes, potentially disrupting genes and causing phenotypic abnormalities. Abnormalities of Chromosome Structure Isochromosomes 1.Isochromosomes are characterized by one arm being missing while the other is duplicated in a mirror-image fashion. 2.This results in partial monosomy for one arm and partial trisomy for the other. 3.The most common isochromosome involves the long arm of the X chromosome, often found in individuals with Turner syndrome. 4.Isochromosomes are frequently observed in karyotypes of solid tumors and hematologic malignant neoplasms. Abnormalities of Chromosome Structure Translocation 1.Reciprocal translocation 2.Nonreciprocal translocation - Robertsonian translocation - Insertion 3. Inversion Abnormalities of Chromosome Structure Translocation 1.Reciprocal translocation - Segments of two non-homologous chromosomes exchange places. - Balanced rearrangement of genetic material (no genetic material is lost or gained). - Causes alternation in gene position. Abnormalities of Chromosome Structure Translocation 2. Nonreciprocal translocation - Transfer of genetic material from one chromosome to another without reciprocal exchange. - This results in one chromosome gaining additional genetic material while the other loses some. Abnormalities of Chromosome Structure Translocation 2. Nonreciprocal translocation - Robertsonian translocation: It involves the fusion of two acrocentric chromosomes (chromosomes with centromeres located near one end). The long arms of the chromosomes fuse together, while the short arms are lost. Abnormalities of Chromosome Structure Translocation 3. Inversion Rearrangement of genetic material within a single chromosome. It involves the flipping or reversal of a segment of DNA within the same chromosome.