WHY DO BIOLOGISTS STUDY BACTERIA, YEASTS, WORMS, FLIES, AND MICE? Harvey F. Lodish, Ph.D. Member, Whitehead Institute for Biomedical Research Professor of Biology and Professor of Bioengineering Massachusetts Institute of Technology

Gene numbers and DNA Content of Representative Types of Cells

All organisms from simple bacteria to complex plants and animals undoubtedly evolved from a common single- celled progenitor

The Central Dogma

DNA is a “code” comprised of a very long linear string of A, T, G, and G “bases” divided into blocks called genes. Each gene “codes for” one protein and contains two segments: One specifies the sequence of amino acids for each of the thousands of proteins the organism can make. Another tells the cell when and in what amount each protein is to be made. The Basics of Molecular Biology Proteins are the working “molecular machines” in cells and organisms. Proteins are strings of 20 different amino acids (“beads”) that are folded in such a way that the protein can carry out is specific function.

We work and think at the level of individual atoms and molecules

Proteins - The Working Molecules of Cells and Organisms Enzymes (Catalyze chemical reactions) Antibodies (Bind foreign objects, such as bacteria) Binding (Hemoglobin in red blood cells) Transporters (Proteins in cell membranes that enable sugars and other nutrients to cross) Structural (Form the internal cytoskeleton and the extracellular matrix) Movement (Contractile fibers in muscle) Bind to DNA (Turn genes on or off) Hormones (send signals fro cell to cell)

Proteins are formed as linear strings (polymers) of chemicals called amino acids Each of the 20 different kinds of amino acids that constitute proteins have the same basic structure, but differ in the chemical properties of the “side chain” or R group.

Nine of the 20 amino acids have side chains that interact well with and dissolve in water. They are said to be hydrophilic (water- loving)

Eight of the 20 amino acids have side chains that interact with and dissolve in oil but not water. They are said to be hydrophobic (water- repelling)

Proteins vary in size, shape, and function (Enzyme) (Antibody)(Binds oxygen) (Hormone)

Many proteins are enzymes, regularly changing their shape as they facilitate specific chemical reactions

Chromosomes, Genes, and DNA

DNA Content of Representative Types of Cells

The Central Dogma

Each amino acid is first linked to a particular type of transfer RNA (tRNA) and is then brought to the ribosome - the molecular machine that incorporates specific amino acids one- at- a- time into the growing protein. By binding specifically to a 3-base codon in the mRNA the tRNA insures that the correct amino acid is incorporated into each position. The ribosome literally walks along the mRNA adding one amino acid for each 3- nucleotide codon in the messenger RNA

The ribosome, a molecular machine that binds to one specific end of the messenger RNA, and then “walks” along the mRNA 3 bases at a time adding amino acids one- at- a- time to the growing protein chain.

The Human Genome Of the ~30,000 genes (thus ~30,000 different encoded proteins) in the human genome 42% have unknown functions 14% are involved in turning genes on or off within the cell nucleus 12% allow cells to communicate with other cells 10.2% are enzymes that facilitate specific chemical reactions 5.0% relate to the fibrous cytoskeleton that gives cells their shape and allows cell movement 4.8% are proteins in cell membranes that allow various chemicals to cross 3.3% allow cells to bind to other cells forming tissues 2.9% are involved in controlling cell division, mainly tumor suppressors 0.9% are involved in functions of the immune system.

Gene numbers and DNA Content of Representative Types of Cells

Bacteria are the smallest and simplest cells

Most of the genes and proteins found in bacterial cells are also found in human cells.

Gene numbers and DNA Content of Representative Types of Cells

Yeasts are among the simplest eukaryotic cells Eukaryotic cells, unlike prokaryotes, have a nucleus as well as many other organelles, compartments that are separated from the cytoplasm by a membrane.

The fission yeast Schizosaccharomyces pombe

The cell cycle in yeast and humans uses the same set of regulatory proteins

The process of cell division is very similar in yeasts and mammals

The division of yeast and human cells uses the same set of motor proteins to move chromosomes into the two daughters.

In metazoan animals groups of cells form into tissues, and multiple tissues form organs

In metazoan animals, plasma membrane proteins bind cells to each other and to collagens and other components of the extracellular matrix

Gene numbers and DNA Content of Representative Types of Cells

White- eye Drosophila mutant

The Eyeless gene is conserved during evolution and codes for the “master gene control protein” that initiates eye formation in both flies and man. Normal (wild- type) Mutant in Eyeless gene

Homeotic Drosophila mutant

The nematode Caenorhabditis elegans

One can trace the fate (lineage) of each of the 929 cells in the worm C. elegans

Watch a cell undergo apoptosis (programmed cell death)

Certain cells in the worm C. elegans are born only to die (top; yellow arrows). Mutation of certain genes abolishes this programmed cell death (bottom; yellow arrowheads)

Comparison of the human and mouse genomes The proportion of mouse genes without any detectable homolog in the human genome (and vice versa) is about 1%. Dozens of local gene family expansions have occurred in the mouse genome, mainly related to immunity, reproduction, and olfaction. These physiological systems have apparently been the focus of extensive lineage- specific innovation in rodents.

Comparison of the human and mouse genomes Both genomes contain ~30,000 protein- coding genes. The mouse genome, 2.5 x 10 9 bp, is 14% smaller than the human genome of 2.9 x 10 9 bp. Over 90% of mouse and human genomes can be partitioned into conserved regions, indicating a common evolutionary ancestor.

Breakdown of mouse proteins according to evolutionary origin Note that only a small fraction of genes are possibly rodent-specific (<1%) as compared with those shared with other mammals (14%, not rodent-specific); shared with chordates (6%, not mammalian- specific); shared with metazoans (27%, not chordate-specific); shared with eukaryotes (29%, not metazoan-specific); and shared with prokaryotes and other organisms (23%, not eukaryotic-specific). Mouse Genome Sequencing Consortium (2002) Nature 420:

Mouse (left) transgenic for human growth hormone

Epo “gene knock- out” mice are normal except that they have no adult- type red blood cells and die at embryonic day 14.