Human Genome Architecture Lecture

Division of Lectures

• Dr. Arshad Ayyaz is the course coordinator.
• His email is [email protected]
• Office hours are available by appointment.
• Email preferred for scheduling.
• Guest lecturer information available via email appointment.
• Dr. Jillian Parboosingh's email is [email protected] , OR [email protected].
• Dr Ryan Lamont's email is [email protected].
• Dr. Timothy Shutt's email is [email protected].
• Stephanie Chieffo's email is [email protected].

The Architecture of Human Genome

• This lecture covers the architecture of the human genome, presented by Dr. Arshad Ayyaz.
• A diagram of human chromosomes is included. Individual chromosomes are labelled from number 1 to 22, the X chromosome and the Y chromosome.
• The image is numbered and shows karyotype.

Objectives of This Lecture

• This lecture will describe and distinguish mtDNA from nuclear DNA.
• It will cover the levels of DNA packaging and organization.
• Identifying key chromosomal components will also be part of the lecture.
• Mitosis and meiosis will be described.
• Students will learn about the number of chromosomes and chromatids before and after mitosis and meiosis.
• Key terms like nucleosome, chromatin, chromatid, and chromosome will be defined.

Lesson Plan

• The flow of genetic information is a major topic covered in this lesson.
• The human genome comprises mitochondrial DNA (mtDNA), nuclear DNA, human genome project (HGP), repetitive DNA sequences, and the organization of nuclear DNA.
• Cell division and chromosomal structure, specifically mitosis (somatic cell division), meiosis (germ cell division), and karyotyping are covered.

Flow of Genetic Information

• DNA is transcribed into RNA.
• RNA is translated into proteins.
• Specific details of the various proteins are included in the presentation.
• The flow of genetic information is from DNA to RNA to protein.

A Gene

• Genes are segments of DNA containing the instructions for protein production in the body.

A Gene (Detailed)

• Genes are DNA segments carrying the code for proteins or molecules.
• These molecules perform specific bodily functions.
• Gene structure includes enhancer sites, which regulate transcription.
• A promoter region contains the TATA box.
• Gene consists of Exons and introns.
• Exons are coding regions and introns are non-coding regions.
• Transcription initiation sites are specified.
• Exons are expressed as part of the mRNA which will be translated to protein.
• Introns are removed/spliced out of the pre-mRNA.
• A poly-A tail is added to the 3' end of the mature mRNA.
• 5' methylguanosine cap is added to the 5' end of mRNA.

Transcription

• Genes can be active (expressed) or inactive.

Post-transcriptional modifications – Splicing

• Introns are removed from the pre-mRNA.
• mRNA (messenger RNA) is transported to the cytoplasm for translation.
• The sequence of nucleotides in mRNA determines which amino acids will be used to make a particular protein in the order required.

Post-transcriptional modifications – 5' Cap and 3' Tail

• 5' cap is a 7-methylguanosine cap
• 3' Poly (A) tail is a series of adenine nucleotides.
• These modifications protect the mRNA from degradation, assist in transport, and signal ribosomes that the molecule is mature mRNA suitable for translation.
• Specific locations within genes are highlighted.

A Tale of Two Genomes

• Human somatic cells have 46 chromosomes, organised in 23 pairs.
• 22 pairs are autosomes, ranging in size.
• The remaining pair are the sex chromosomes: XX for female and XY for male.

Mitochondrial DNA (mtDNA)

• mtDNA is circular and does not include introns.
• mtDNA is inherited from the mother.
• It contains 37 genes coding for 2 rRNAs, 22 tRNAs, and 13 proteins, which support oxidative phosphorylation in cellular respiration.
• MtDNA is responsible for mitochondrial-specific transcription and translation

The Organization of Human Mitochondrial Genome

• mtDNA has heavy (H) and light (L) strands.
• The D loop, or displacement loop is a triple stranded region with 7S DNA.
• The D-loop includes the mtDNA control region which includes the promoter region.
• Variation in the number of mtDNA copies occurs between cell types.

Maternally Inherited Diabetes and Deafness (MIDD)

• MIDD affects approximately 1% of diabetic patients and is more common in the Japanese population.
• Mutations in mitochondrial genes, specifically MT-TL1, MT-TK, or MT-TE, lead to reduced tRNA activities.

Nuclear (Chromosomal) DNA

• This section focuses on nuclear DNA details.

Human Genome Projects (HGP) - 1990-2003

• The HGP aimed to map and understand all human genes.
• Strategy: sequence 500 bases at a time.
• The structure of a gene was highlighted, including the promoter region, exon, intron regions.
• Techniques such as fragmentation and cloning were mentioned.

Human Genome Projects (HGP) - 1990-2003 (Detailed)

• The project aimed to map and understand all human genes.
• The genome is about 3.1 Gb.
• Less than 1.5% encodes proteins.
• Repetitive DNA sequences make up the majority of the genome.

Reference Human Gene Sequence

• The reference human gene sequence is described. Included in the image is a summary of how single nucleotide polymorphisms (SNPs) are identified.

Number of Coding Genes

• Statistics from NCBI and GENCODE genome annotations: Data included the total number of genes, protein-coding transcripts, non-coding pseudogenes and total pseudogenes.

Human Genome Annotations (variable)

• Human genome annotations are described in depth.

An Example of Read-through Transcription

• Some genes make protein-coding mRNAs and functional noncoding RNA transcripts.

Complete Human Genome?

• Long-read sequencing is used to read larger stretches of DNA.
• The first 92% of the human genome was relatively straightforward to sequence.
• The final 8% proved more challenging, especially repetitive regions within the sequence.

Types of DNA

• Single copy DNA.
• Repetitive DNA
• Dispersed repetitive DNA.
• Satellite DNA

Repetitive DNA Sequence

• Specific types of repetitive DNA are explained (e.g. Alpha-satellite, Minisatellites, Microsatellites).
• Practical applications of these repetitive elements in areas like forensic identification and cancer research are included.

Dispersed Repetitive DNA Sequence

• SINEs, LINEs and segmental duplications are described.
• How these repetitive elements can be implicated in gene disruption

How does DNA package into a nucleus?

• DNA is wound up to form nucleosomes using histones.
• Nucleosome formation is followed by tightly coiled solenoids and finally forming a chromatin loop

Levels of DNA Packaging into a Chromosome

• The 3 billion base pairs of DNA are packaged tightly, beginning as DNA tightly wrapped around proteins. This results in a highly compact form.

Cell Division – Mitosis and Meiosis

• Mitosis is necessary for somatic (body) cell division.
• Meiosis is instrumental in gamete (sperm and egg) formation.

Mitosis (Somatic) Cell Cycle

• Stages of mitosis, including interphase (G1, S, G2) and the mitotic phase are depicted.

Mitosis

• Mitosis involves chromosome condensation.
• Chromosomes are dynamic structures.
• Stages of mitosis, including interphase to cytokinesis, are shown.
• Mitosis ensures identical genetic material is passed on to the resulting daughter cells.

The Human Karyotype (Karyogram)

• Describes chromosome components, like telomeres, short and long arms, and the centromere.

Chromosome Classification

• Describes the classification of chromosomes, including metacentric, submetacentric, and acrocentric based on their centromere position.

Size and Gene Content of Human Chromosomes

• The size and gene content of each chromosome pair are presented.

Ploidy

• Ploidy refers to the number of copies of each chromosome.
• In human somatic cells, the number of chromatids is often indicated by the letter “c”.

Number of Chromosomes and Chromatids

• Explains the relationship between "n" (haploid) and "2n" (diploid) sets of chromosomes.

Ploidy and Chromosome Number (Meiosis and Mitosis)

• Shows the ploidy changes during meiosis (reduction division for gamete formation) and mitosis (for somatic cell division).

Meiosis

• Meiosis is responsible for gamete production in the body (egg and sperm).
• Meiosis includes two divisions which reduces chromsome quantity.
• Key consequences of meiosis are recombination, random assortment and segregation.

Meiotic Nondisjunction

• Failures in meiotic segregation can cause genetic disorders.
• In meiotic nondisjunction, homologous chromosomes or sister chromatids fail to separate properly during meiosis.

Any Example of Good Mutations?

• Lactose tolerance is an example of how mutations can result in beneficial phenotypes.