Human Genome Complexity and Comparisons

Genome Comparisons

• The human genome has a greater information content than other species with around 25,000 protein-encoding genes.
• Despite having similar numbers of genes, C.elegans and Arabidopsis have significantly smaller genomes, and Wheat has a significantly larger genome due to polyploidy.

Human Genome

• The human genome contains more information than just the 25,000 genes, thanks to transcriptional and translational complexity.
• The human proteome contains over 100,000 proteins due to alternative splicing, post-translational modifications, and multiple proteins made from one gene.

Human Genome Complexity

• Human genome complexity stems from multiple transcriptional start sites per gene, alternative splicing, complex non-coding regulatory regions, and extensive post-translational modifications, including glycosylation.

Take Home Message

• A single gene can encode multiple proteins, meaning the 25,000 genes in the human genome can produce over 100,000 proteins.

Human Genome Content

• 1% of human DNA encodes proteins.
• 4% of DNA encodes non-coding RNAs.
• 95% of DNA is made up of transposable elements, repeats, heterochromatin, and other sequences.

Gene Families

• Gene families are groups of closely related genes arising from a single ancestral gene.
• These genes are called paralogues and often cluster together on chromosomes.
• Gene families originate from duplication events.

Mechanisms of Gene Duplication

• Tandem Duplication: Unequal recombination during crossing-over, leading to duplication and deletion events.
• Translocations: Exchange of DNA between chromosomes, resulting in duplications in new chromosomal locations.
• DNA Polymerase Slippage: Small duplications and deletions during DNA replication.
• Transposable Elements: Mobile DNA elements, categorized as retrotransposons (copy and paste) or DNA transposons (cut and paste).
• Whole Genome Duplication: Polyploidy, extra copies of chromosomes.

Gene Duplication Effects

• Redundancy: Genes with the same function, loss of one has minimal effect, loss of both has significant effect.
• Specialization: Duplicated genes acquire novel or specialized functions.
• Degradation: One copy may degrade due to mutation, resulting in a pseudogene.

Duplication and Redundancy

• The loss of one duplicated gene may have little or no effect, as the other performs the same function.
• Loss of both copies can have significant effects.
• Degradation of one copy can occur without selection pressure resulting in a pseudogene.

Duplication and Specialization

• Mutations can alter the activity or expression of duplicated genes, leading to specialized functions.
• The new gene may have a unique function vital for survival.
• Selection against mutations that eliminate this new function.

Example: Hox Gene Family

• Homeobox transcription factors differentially expressed along the body axis during development.
• They give identity to developing tissues in different parts of the body.
• Different species have varying numbers of Hox clusters: invertebrates have 1, humans have 4, and fish have 7.

Hox Gene Redundancy

• Loss-of-function mutations in Hox genes are lethal in Drosophila but cause subtle effects in humans.
• HOXD13 mutations can result in shortened or fused fingers.

Example: Hyaluronidases

• Enzymes that degrade hyaluronan, a key component of extracellular matrix.
• Nematodes have one hyaluronidase, while humans have two clusters of three paralogues each, with different enzymatic activities and tissue expression patterns.
• Loss of a HYAL gene leads to subtle defects, such as accumulation of hyaluronan and lysosomal storage disorders.

Micro RNAs (miRNAs)

• miRNAs regulate gene expression by binding to target mRNA molecules.
• They are important regulators of gene expression and are involved in various biological processes.
• miRNAs are negative regulators of gene expression, leading to translational repression or mRNA degradation.
• They are implicated in various human diseases.

Bias in Human Genomics Studies

• Most human genetic studies focus on people of European ancestry, leading to a limited understanding of human genetic diversity.

Human Genome Diversity

• African populations have more genetic diversity than any other group.

Summary of RNA Classes

• Different classes of RNA have different functions, such as messenger RNA, ribosomal RNA, transfer RNA, small nuclear RNA, long non-coding RNA, micro RNA, and small nucleolar RNA.

What is a Gene?

• The definition of a gene has broadened, encompassing DNA sequences that encode both proteins and non-coding RNAs.
• Gene boundaries can be difficult to define, as regulatory elements can lie within or even outside of genes.
• Genes can be nested within each other, and multiple genes can be co-transcribed.

Summary of Objectives

• Understanding the content of the human genome, including protein-encoding genes and non-coding RNAs.
• Learning how gene families evolve through duplication events, leading to redundancy, specialization, and pseudogene formation.
• Recognizing the complexities of defining what constitutes a gene.

Explore the intricacies of the human genome and its complexity compared to other species. Discover how human genes lead to a diverse proteome through various processes like alternative splicing and post-translational modifications. Delve into the genome size differences among species and the significance of gene encoding.