The Old Man and the Cats with Six Toes

Famed author Ernest Hemingway was fond of polydactyl (six-toed) felines, and introduced them onto his estate in Key West, Florida. Their mutation springs from a fault in a deoxyribonucleic acid (DNA) “control switch,” and not from an error in the gene itself. The “letters” of DNA – A, C, T and G – stand for the chemical “bases” of adenine, cytosine, thymine and guanine. These string together in the familiar double helix in most cells in your body. In 1953, molecular biologists Francis Crick and James Watson deciphered the ladder-like double helix shape of the DNA molecule. The bases that compose the ladder’s “rungs” always pair together – A with T and G with C. Scientists call the specific order of the bases a “sequence.”

“We are not solely products of nature or nurture – we’re shaped by both, and they are inextricable from each other.”

Chromosome Pairs

The 46 strings of DNA form into “23 pairs of chromosomes” inside each of your body’s cells; these constitute your genome. Women have two X chromosomes; men have an X and a Y chromosome. The chromosomes reside in the middle of the cell – in its nucleus. This is the DNA “library” from which “RNA polymerase” copies DNA to “messenger RNA,” which then carries encoded protein-building instructions to “ribosomes.” This process is called “translation,” because it renders each three-letter “triplet” of the RNA’s code into one of 20 specific amino acids.

“’The human genome’…is an idealized genetic Bible for our species, cobbled together from a handful of people. The DNA in your body differs from that script in millions of ways.”

You get one copy of each gene from your mother and one from your father. When a sex cell (an egg or sperm) forms, the genes get “mixed around.” Receiving a “faulty gene” from one parent may do you no harm, but sometimes – as in cystic fibrosis – receiving faulty copies of the same gene from both parents causes serious problems.

“There’s no such thing as the perfect human genome...You have yours, I have mine, everybody else has theirs.”

Genomes

A genome is a DNA schematic for building an organism – a set of instructions that tells cells to make molecules. The genetic instructions which guide the molecules and cell specializations that build a human being are set in motion when a sperm meets an egg.

“The genome as we understand it today is a dynamic, writhing library, buzzing with biological readers and writers.”

In 1976, scientists published the first complete genome. By 1995, scientists sequenced a whole bacterium genome. In 2001, the Human Genome Project announced the first working draft of the human genome. Surprisingly, at around 20,000 genes, humans have fewer genes than other, apparently simpler, organisms. In evolutionary terms, people arrived recently and developed from a gene pool of a small number of individuals. Compared to other organisms, humans aren’t genetically diverse. Evolution shaped humankind’s genomes. Biology is chemistry, and it’s random. The human genome is messy, with both “functional” DNA and apparent “rubbish” DNA between genes.

“Within your genome there are sequences that should be as dead as a doornail, yet they arise and start walking. Or rather, jumping.”

The “Switches” of Life

Molecular switches – or “repressor” proteins – outside of a gene controls its “on/off” state. This gives rise to a “genetics-as-electronics” theory. You contain many types of cells – brain, skin, muscle, and more. Most human genes stay “switched off” until required. For humans, the question is more one of gene “activation” than of gene “repression.”

“So, that’s your genome as we now know it: a genetic garage packed with junk, garbage, control switches and a few thousand ‘proper’ protein-making genes dotted about in all the mess.”

Molecular biologist Mark Ptashne ponders how “genetic switches” activate genes at the right time and in the right way during development. He studies how small differences in protein-coding genes between, say, humans and chimps, lead to different characteristics. He credits much of this to “gene regulation” – the differences in the switches that emerged during evolution. Some factors are selective; others are quite “promiscuous.” Over time, the degree of “cooperativity” among these factors affects the ease of binding, which affects gene switching, which alters organisms. Genetic switches are not always near (in DNA terms) the genes they control. A fault in one letter in a switch of around 800,000 DNA letters in a gene which that switch controls gives a Hemingway cat its extra toe. No gene “makes a toe.” But cells cannot know what they are to become without appropriate messaging. With incorrect switching, cells may misplace and mis-time their growth in a developing limb – hence the mutation, which affects other creatures’ limbs in different ways.

“We’re all walking around with a handful of potentially dangerous or even deadly gene faults, as well as millions of random little differences peppered throughout our genome.”

Stickleback Fish

Stickleback fish that became trapped in lakes away from an ocean environment developed “physical differences” from sea-native, three-spined sticklebacks. The main difference is their lack of a “pelvis-like structure” with spiky rear fins. Safe from sea-dwelling predators, lake sticklebacks didn’t need that weaponry. The mutation survived in their protected lake environment and, over time, gave rise to the new trait. Physical changes due to evolution are slow, but this was relatively quick – it happened over a mere thousands of years. For instance, tiny changes in a switch affecting the “Kitlg” gene in humans controls melanin pigment levels; the diversity in human skin color arose relatively recently in evolutionary terms.

“Biology is not binary. Switching genes on and off isn’t like flicking a light switch up or down, flipping from pitch black to blazing light. It’s more like a dimmer dial.”

Only around 1% of human DNA differs from that of chimpanzees. Something else must cause the differences: switches. Mammals share a strong similarity in protein-coding genes, but their hard-to-identify switches vary enormously. The fast rate of change in switches – such as the development of “lactose tolerance” – is a factor for humans. So is the effect of technology on the rate of change. Fast, diverse genetic adaptations may make humans more resilient, not weaker.

“Some examples do seem to hold up in terms of a real effect, such as measurable changes in stress hormone levels in the 9/11 women and their babies.”

“Nightlife”

All the “exciting” nightlife in a nucleus “city” happens in the center. Genome biologist Wendy Bickmore – who studies DNA in the nucleus using a “DNA painting” technique – likes this metaphor, since it describes how more “active” chromosomes congregate near a nucleus’s middle. Some scientists think that switches loop over to touch the genes they control. Bickmore maintains that it happens through indirect, messy “mass action” – in “blobs,” not in neat “loops.”

“Every single cell in your body contains more than two meters (six and a half feet) of DNA. Yes, you read that right. Two meters.”

“Epigenetics”

The idea behind epigenetics is that something extra shapes you, beyond your “basic genetic code.” In terms of the old debate, “nature” is your DNA and “nurture” is the effect of your environment. But epigenetics blurs that dichotomy by introducing potential ways – including “DNA methylation” – for your environment physically to supplement or modify your genetic code. Methylation might shut some genes off. Your children could then inherit these genes carrying within-lifetime modifications. Environmental effects – like the stress that a traumatic event has on a parent – may pass to the child. Though cells can retain “tags” – a type of “memory” of previous states – little evidence shows any large effects from methylation changes.

“Small changes in genetic control switches can have profound effects.”

Genome Splicing, Editing and Tuning

In comparison with bacteria’s efficient genomes, the genomes of humans and other complex organism appear messy and junk-laden. While studying the common cold virus, researchers Rich Roberts and Richard Gelinas discovered that virus genes work differently than bacterial genes. Using “electron microscopy,” they saw that, unlike in bacteria, strands of viral DNA did not match exactly with the strands of their paired RNA messages. During “RNA splicing,” “spliceosome” proteins edit down “too-long” messages from genes, eliminating noncoding text (called “introns”) and sticking the protein-coding “exons” back together. Depending on how genes splice, they produce different proteins. Like a “recipe,” the same instructions can work with different options to make alternate versions.

“A single DNA letter change – from an A to a G – gives the Hemingway cats their thumbs.”

Some genes encode for “neurotransmitter receptors” in the brain. Scientist Peter Seeburg discovered that large-scale “RNA editing” takes place in these receptors, and this seems vital to brain function. In people suffering from ALS – Lou Gehrig’s disease – this editing fails. Brain “motor neurones” no longer switch properly, and begin to die. Investigations continue into gene therapies that are intended to boost the motor neurone editing activity. Geneticist Billy Li thinks “flexibility” arising from editing is central to brain “capacity.” At Stanford, professor Julia Salzman and her team investigate “fusion genes.” These genes aren’t related, but they blend to create a cancer-contributing combination such as the leukemia-causing “Philadelphia chromosome.” In 2012, Salzman published a paper showing the existence of “circular RNAs” – “scrambled” messages with their ends located before their starts. The brain has many circular RNAs, but no one understands their purpose. RNA is clearly not “passive.”

“Nobody designed biology, and life does not run like a slick machine.”

“Gene Silencing”

In today’s “molecular biology revolution,” editing genes is becoming possible. Experimentation in this area found “cosuppression” or “quelling,” in which adding more copies of certain genes turns them off instead of exaggerating their effects. “Sense” and “antisense” RNA experiments showed anomalous, random, counterintuitive suppression effects. In “RNA interference” (RNAi), tiny lengths of “paired RNA” produce dramatic gene silencing. Further findings are always emerging: RNAi is a factor in developing therapeutic drugs, “micro-RNAs” may “fine tune” gene activity and “pi-RNAs” add to the complex picture of noncoding RNA.

Jumping Monkey Genes

Unlike other South American monkeys, owl monkeys are resistant to HIV. Like African and Asian monkeys, they have the “Trim5” gene that blocks HIV multiplication. Because a gene called “CypA” once “hopped” into Trim5, these monkeys are immune to HIV. But most “jumping genes” – called “transposons” – aren’t so useful. Most of the time, DNA methylation protects mammals’ DNA from transposons, though it’s vulnerable during fertilization. The transposon “Line-1” may help give brains their “uniqueness.” Like everyone else, you have “zombie genes” in your genome. Until recently, scientists considered the 10,000 or so “pseudogenes” in the human genome to be “dead genes.” Some don’t stay dead. Sometimes, “retrotransposition” pastes RNA back into the genome, which is later read into functional RNA. A “long noncoding RNA” from a pseudogene helps calm the body’s inflammation response.

Random events affect gene activity. Although biology is robust, this “wobbliness” and its consequent errors mean that science can offer no guarantee that even simple clones will emerge completely identical. Environmental factors play a major role in shaping differences.

“Virgin Births”

Virgin births, or “parthenogenesis,” occur in some fish, in many insects and some lizards. DNA from the female alone is enough to produce offspring. Attempts to produce parthenogenetic offspring from mice failed because of “imprinting,” which appears to “mark” differentially the sex origins of the DNA in species that are not parthenogenetic.

From “Genotype” to “Phenotype”

While studying Down’s and DiGeorge (“velocardiofacial”) syndromes, research scientist Gholson Lyon noticed variation in symptoms. He saw in-family symptom variation in victims of Ogden syndrome – a disorder that leads to the deaths of baby boys due to a gene fault on their lone X chromosome. Everyone has gene faults, but most of these faults don’t lead to mutations, so “genetic background matters.” The human genome as scientists have mapped it so far is simplistic. A “whole genome” of the combined genomes of every human ever born would clarify the picture. Companies like 23andMe now map individual genomes cheaply.

“Mishmash”

Botanist and scientist Gregor Mendel’s 1865 paper laid the scientific foundations of the idea that offspring get two versions of each trait – one from each parent – and that some traits are dominant and others are recessive. Geneticists now know that the picture isn’t that clear-cut. Offspring don’t get an even split of traits. They get a mishmash – as if a “black box” of complexity exists between the genotype (the DNA code) and the phenotype (the outcome as a living organism).

What Is a Gene?

What is a gene, anyway? Headlines about genes take people in, but the term itself is vague. Time, mating and randomness throughout evolution produces genomes; traits survive only if organisms breed. The genome is like a box of Lego toys, with many possible configurations.