BMS8110复习（三）：Lecture 3 - Introduction to Genomics

What is Genome?

• A genome is the genetic material of an organism.
• It consists of DNA (or RNA in RNA viruses). The genome includes both the genes (the coding regions) and the non-coding DNA, as well as mitochondrial(线粒体) DNA and chloroplast(叶绿体) DNA.
• Genes provide the information for making all proteins that are necessary for the expression of characters (phenotype).
• Gene ---->  Protein(RNA)  ------> Phenotype
• Phenotype refers to how an organism looks, its physiology, its ability to fight infections and even its behavior.
• Phenotype traint - both macroscopic(宏观的) and molecular - depend on a combination of influences from genome sequences, the individual's life history and epigenetic signals in the fertilized egg(受精卵). 

Prokaryotic vs Eukaryotic cells：

• 真核细胞指含有真核的细胞，其染色体数在一个以上，能进行有丝分裂，还能进行原生质流动和变形运动。
• 由真核细胞构成的生物称为真核生物，在真核细胞的核中，DNA与组蛋白等蛋白质共同组成染色体结构，在核内可以看到核仁。
• 原核细胞指没有核膜且不进行有丝分裂、减数分裂、无丝分裂的细胞，这种细胞不发生原生质流动，观察不到变形虫样运动，组成原核生物的细胞，这类细胞，主要特征是没有明显可见的细胞核，同时也没有核膜、核仁，只有拟核，进化地位较低。

What is Genomics?

• Genomics is the study of the genome, including interactions of those genes with each other and with the organism's environment.
• How is Genomics different from Genetics?
  • Genetic looks at single genes, one at a time, like a picture or snapshot.
  • Genomic looks at the big picture and examines all the  genes as an entire system.

Components of the Human Genome

• Genes (coding sequences + introns(内含子) + UTRs(非编码区))
• Regulatory elements (promoters, enhancers, insulators, repressors)
• Other non-coding regions
  • Pseudogenes(假基因)
  • Genes for noncoding RNA (nc RNA)
  • Repetitive DNA sequences
  • Mobile genetic elements (transposons) and their relics

Genes and Proteins

• Introns: Derived from the term "intragenic(基因内的) regions", are non-coding sections of precursor mRNA (pre-mRNA).
• Exons: Are coding sections that remain in the mRNA sequence.

Pseudogenes

• Pseudogenes are inactive copies of protein-coding genes, often generated by gene duplication, that havve become non-functional through the accumulation of inactivating mutations.
• The number of pseudogenes in the human genome is on the order of 13,000 and in some chromosomes is nearly  the same as the number of functional protein-coding genes.
• Gene duplication is a major mechanism through which new genetic material is generated during molecular evolution.

olfactory(嗅觉) receptor gene (pseudogenes) 典型的人体假性基因

人类60%的基因是无功能的假性基因；而小鼠只有20%。这也是为什么人类嗅觉没有很多动物敏感。

ncRNA Genes

• Non-coding RNA moleculars play many essential roles in cells, especially in the many reactions of protein synthesis and RNA processing. 
• Non-coding RNA includes tRNA(转移核糖核酸), ribosomal(核糖体的) RNA (rRNA), micro RNA 小分子核糖核酸, snRNA and other non-coding RNA genes including about 60,000 long non coding RNAs (lncRNAs)
• Many ncRNAs are critical elements in gene regulation and expression.

Xist (X chromosome inactivation) X染色体失活特异转录因子

Regulatory Elements

• Promoters
  • A promoter is a region of DNA that leads to initiation of transcription of a particular gene.
  • Promoters are located near the transcription start sites of genes, upstream on the DNA
  • Promoters can be about 100-1000 base pairs long.
• Enhancers
  • An enhancer is a short (50–1500 bp) region of DNA that can be bound by proteins (activators) to increase the likelihood that transcription of a particular gene will occur.
  • These proteins are usually referred to as transcription factors. Enhancers are cis-acting
  • They can be located up to 1 Mbp (1,000,000 bp) away from the gene, upstream or downstream from the start site.
  • There are hundreds of thousands of enhancers in the human genome.
  • They are found in both prokaryotes and eukaryotes
• Insulators
  • An insulator is a genetic boundary element that blocks the interaction between enhancers and promoters
  • It is thought that an insulator must reside between the enhancer and promoter to inhibit their subsequent interactions.
  • Insulators therefore determine the set of genes an enhancer can influence.
• Repressors
• 

Transposons(转座子)

• The sequence of human genome emphasizes the importance of transposons
• Most of the transposons in the human genome are nonfunctional; very few are currently active
• They have played an active role in the shaping the genome
• Some present genes originated as transposons, and evolved into their present condition after losing the ability to transpose.
• Almost 50 genes appear to have originated like this.

We need genomic information to 

• improve human health
• harness natural energy
• understand and react in a positive manner to global climate change
• clean up our environment and 
• ensure food safety

High throughput seqencing: DNA sequencing techniques enables scientists to determine the exact order or sequence of the bases of a genome.

The Human Genome: The DNA material is organized into a haploid chromosomal set of 22 and a sex chromosome.

The total number of genes is estimated at approximately 20,000 ~ 25,000 genes in the human genome.

Almost all (99.9%) nucleotide bases are exacty the same in all the people.

Mutation and disease

• Most mutations causing amino acid sequence changes are harmful, impairing protein function and threatening to produce disease.
• Some mutations destroy activity of a protein e.g. haemophilia(血友病) arise from mutation of blood coagulation(凝固) factor VIII or IX.
• Mutations that destabilize proteins can increase proportion of misfolded proteins that form aggregates in Alzheimer's disease, Huntinton's disease, Prion diseases.
• OMIM: Online Catalog of Human Genes and Genetic Disorders

Single nucletide polymorphisms (SNPs 单核苷酸多态性)

• SNPs are the most common type of genetic variation among people.
• Each SNP represents a different nucleotide. For example, a SNP may replace one C with one T.
• SNPs occur normally throughout a person's DNA, once in every 300 nucleotides on average (mostly in non-coding regions), which means there are roughly 10 million SNPs in the human genome.
• They can act as biological markers where associated with diseases.

Haplotype（单倍型）

• A haplotype is a group off genes in an organism that are inherited together from a  single parent.
• A haplogroup(单倍群) is a group of similar haplotypes that share a common ancestor with a single-nucleotide polymorphism(多态性) mutation.
• Many human genetic testing companies use the term 'haplotype' to refer to an individual collection of specific mutations within a given genetic segment.
• In looking for genes responsible for diseases, haplotypes provide a magnifying glass to correlate phenotype with genome sequence.

International HapMap Project

Major histocompatibility complex (MHC)

Sequencing the genome of other organisms

Genomics and development biology

• Genomes contain development programs governing expression patterns of genes at different life stages, in differentiated tissues and reactions and responses to environmental stimuli.
• Developmental toolkit: sets of genes active in guiding development

Organization of chromatin structure

Mapping histone modifications

Genome browsers

• Databases dealing with full genome sequences
• Designed to organize and annotate genome information
• Present via webpages with links to related data
• Provide tools for searching and analysis
• 2 major genome browsers:
  • Ensembl (Sanger Centre & European Bioinformatics institute, UK)
  • UCSC (University of California at Santa Cruz, USA)