The Thousand Dollar Genome Has Arrived!

The first human genome was sequenced about a decade ago, at a cost of around four billion dollars. The results were amazing, showing us that people have a paltry twenty some thousand total genes. We thought we were a lot more complicated than that. We also found that chimps have DNA sequence about 99% identical to ours. Ouch again! We thought we were more special than that.

OK, we sequenced the human genome, and learned some cool stuff. So, you might think, end of story, now let’s do something else.

But the sequencing of one human genome is really just the beginning of the story. Different people have DNA sequences that are about 0.1% different. Unless they are twins. And twins are remarkably alike, in appearance and just about everything else, exactly because they share the same DNA sequence. The obvious conclusion is that your DNA sequence is really important in defining your many traits.

We’d like to be able to unravel the very complicated relationship between your DNA sequence and your traits. Many diseases have a foundation in DNA sequence. If we knew which of your genes contributed to your disease then we might be able to devise more effective therapies, designed to work best for you.

We’d like to sequence the DNAs of lots of people, with many different illnesses, to better understand the genetic basis of disease. But at four billion dollars per sequence that’s not going to happen.

Enter the DNA sequencing revolution! The cost of sequencing a person’s DNA has been plummeting. A year ago it cost only about four thousand dollars, down a million fold from the original four billion dollars. But even four thousand dollars is still a lot of money.

But, Illumina has just announced a new machine, the HiSeqX Ten, capable of sequencing a person’s DNA for only 800 dollars. Further, it offers staggering throughput, capable of sequencing tens of thousands of genomes per year.

The thousand dollar genome has long been considered the cost point at which genome sequencing can become a standard diagnostic procedure. We are now entering an era where everyone will have their DNA sequenced, and the resulting data will become a key part of our medical records.

As we collect thousands, and then millions of DNA sequences, and correlate them with the corresponding medical records, we will figure out how the different sequences contribute to disease. Medicine is about to take a giant step forward.

And, in a similar manner, we will begin to better understand how DNA sequences impact our other traits, including intelligence, appearance and athletic ability. When this new understanding is combined with our increasing power to manipulate our DNA sequences it opens up some fascinating, and perhaps frightening, possibilities. We will be the first species able to dictate our own evolution.

The term eveloce refers to a singularity boundary point in our evolution, where each generation is more intelligent, and better technologically equipped, to genetically design the next generation. A literal evolutionary explosion results.

And where this will take us, nobody knows. It could well mean the end of the human race as we know it, but perhaps the beginning of something better.

A Genome Without the Junk Proves that ENCODE Conclusions are Garbage

One of the shocking results of the Human Genome Project was the finding that we only have about 20 thousand genes. This seemed a ridiculously small number to encode an organism as complex as a person. How does a fertilized egg turn itself into an adult human being when it is only equipped with some 20 thousand genes in its nucleus to guide the process??

You might think that if people have 20 thousand genes then other organisms must have far fewer. We’re better than them, right? You’d think it would take more genes to make a person than a mouse, or a frog, or a fruit fly. But it turns out that all mammals have pretty much the same number of genes. And many amphibians have more genes than us. And fruit flies have about 15 thousand genes, a number not way different from us. It is clear that we are not at the apex of the chart when it comes to gene number.

It turns out that only about one percent of our DNA is encoding protein, the prime function of genes. The proteins are the workers, making muscles move, breaking down food, creating energy, and building the backbones of our cells. DNA is the sacred data storage unit, passed from one generation to the next, carrying the code that tells cells how to make proteins. But if genes make up only one percent of our DNA, then what does the rest of the DNA do??

There are competing theories. Some scientists say most of this extra DNA is just junk. It exists, but it does no harm, and we live with it. It is excess baggage that we carry around. But others contend that most DNA actually has function, perhaps in creating very fine regulatory networks to make sure that the genes are properly expressed.

To better understand the function of the noncoding DNA the US National Institutes of Health funded the ENCODE project, the Encyclopedia of DNA Elements. Hundreds of scientists were put on the job, hundreds of millions of dollars were spent, and some of the results have now been published in the most prestigious journals. They were looking for the function of this extra DNA, and they loudly proclaimed that they had indeed found it. And it was not junk! Indeed, based on their studies they concluded that at least 80% of the DNA, not just the 1% encoding proteins, has important function in at least some cell type.

So, one might think, problem solved.

But then an international consortium of 29 scientists published a study of a rather remarkable plant, U. gibba. They are bladderworts, often compared to snapdragons and orchids, and they are carnivorous, trapping and digesting prey organisms. It turns out that U. gibba has a very surprising genome, with almost no junk DNA. The results were so unexpected that the paper was published in Nature (June 2013), one of the most prestigious journals. It turns out that the U. gibba DNA has 28,500 genes, significantly more than human DNA, but the total amount of DNA per cell is only 77 megabases, about 40 times smaller than ours. So, while there are far more protein encoding genes, there is far less DNA. There is almost no junk!

And it is not something peculiar to plants. Most plant DNAs are like most animal DNAs, with only a very small percentage consisting of genes. An evolutionary comparison of the U. gibba DNA with DNAs from related plants, including tomatoes and snapdragons, shows that the U. gibba has somehow figured out how to eliminate the excess DNA. And yet is does just fine! It doesn’t need the junk!

The unavoidable conclusion is that the extra DNA is not required. It has no essential function. It is really just junk. And ENCODE is wrong.

The Twenty Missing Genes

We people have about twenty five thousand genes, a shockingly small number considering how complicated we are. It is truly amazing that you can genetically encode all of the remarkable complexity of a person with only twenty five thousand genes.

As we sequenced the DNAs of other organisms we discovered that people don’t have a particularly large number of genes. Indeed, all mammals have almost exactly the same number as us, with the precise base sequences of the genes varying somewhat from one species to another. Several fish and amphibians actually have quite a few more genes than us.

Some of our twenty five thousand genes are of critical importance. If you inherit even a single bad copy of the Huntington’s disease gene, for example, then you are quite doomed. Certain regions of the brain will begin to die, usually in middle age, resulting in jerky involuntary movements and mental decline. There is a slow inexorable progression to dementia and death.

For most genes if you have one good and one bad copy then you are fine. But two bad copies can spell disaster. For example two bad copies of the HPRT gene causes Lesh-Nyhan syndrome, a horrible condition that includes self mutilation behaviors, with head banging, finger biting and lip biting. It is not unusual for people with Lesh-Nyhan to actually bite off their own lips and fingers.

The ongoing innovation in DNA sequencing is allowing us to learn more about the functions of specific genes. While the sequencing of the first human genome took many years and cost about four billion dollars, it is now possible to sequence a person’s DNA in a week or so, for under five thousand dollars. As a result we are collecting the DNA sequences of thousands of people, and before long it will be millions.

As we analyze these many DNA sequences and relate them to the features of the people they came from, including health and disease, intelligence, appearance and athletic ability, we will begin to crack the genotype/phenotype code. In time we will figure out which sequences cause which traits.

One of the early surprises from these types of studies is that we all carry a surprisingly large number of bad genes. A research article recently (Feb 2012) published in the prestigious journal “Science” describes “A systematic survey of loss of function variants in human protein-coding genes”. They examined the DNA sequences of 185 people, and found that on average a person has about 100 nonfunctional genes. And for about twenty of these genes both copies are “completely inactivated” by mutation. This is a bit of a shock, to realize that we are each of us walking around with about twenty completely dead genes, with both copies not working.

What does it mean? Well, for one thing it reminds us that not all genes are equally important. While some genes are critically important, there are clearly other genes that we can live without.

Nevertheless, it is unmistakable that we all carry a lot of genetic baggage. In addition to these completely nonfunctional genes we each have millions of SNPs, or single nucleotide polymorphisms, many of which can alter the functions of our genes, although not completely inactivate them.

It would seem that the way that we now make babies, although lots of fun, is really a game of Russian roulette. Bad gene combinations are probably the main reason why only about half of fertilized eggs actually make it to birth. Most of the rest die very early, before implantation into the wall of the uterus, and before the Mother even knew she was pregnant.

There is a perfect storm of ongoing revolutions in the fields of DNA sequencing, stem cells and genetic engineering that will soon allow us to take chance out of the equation. It will be possible to take skin cells and turn them into stem cells, and then to genetically engineer them to carry the DNA sequences that will produce the desired traits, including health, longevity, intelligence and appearance. Stem cells from the father can be turned into sperm, and those from the mother used to make an egg. The end result would be a designer genes baby, with a full set of functioning genes.

Such self-directed genetic engineering of our DNA could result in a dramatic and rapid transformation of our species. Indeed, it could mean the end of the human race as we know it, but perhaps the beginning of something better.

About the author:
Eveloce is a term coined by Steven Potter to stand for self accelerating evolution. It is derived from the words evolve and veloce, which is Italian for rapid. As we learn how to make smarter people, then those people will do an even better job of making still smarter people, and so on.
Steven Potter, PhD, is a professor at Children’s Hospital Medical Center in Cincinnati. He has published over one hundred research articles and co-authored the third edition of Larsen’s Human Embryology, a medical school textbook. He also wrote Designer genes: a new era in the evolution of man, published by Random House.

Why are people different from chimps??

Compare the DNA of two people and you see about three million base sequence differences and compare the DNA of a human and chimp and you see about thirty million. This is out of about three billion bases total. So, at the DNA level, people are about 99.9% identical to each other and about 99% identical to a chimp. This just counts single base differences, and not copy number variations and such, but in general it is clear that we are remarkably similar at the DNA level to chimps.

So why are we so incredibly different from chimps?

One view is that we really are not that different. Oh sure, we have Apple computers, Rocket Scientists and Astrophysics. But maybe if you could just tweak a chimp’s brain a tiny bit, and give him language, and books, and a few thousand years, then maybe chimps could have that stuff too.

It is interesting to note that it was recently shown that even bird-brained pigeons have a surprising ability to do some rather sophisticated math reasoning.
http://news.sciencemag.org/sciencenow/2011/12/no-joke-pigeons-ace-a-simple-math.html?ref=em&elq=b8eb6ef977d446e3bc710203e26926f8
We like to think that humans have a monopoly on thinking and reasoning, but we don’t.

But our brains are three times bigger than a Chimps!!

But are big brains all that they are cracked up to be? A sperm whale brain weights 7800 grams, an elephant brain weighs 7500 grams and a person’s weighs 1500 grams. Are whales and elephants really that much smarter than us?

And are those people with bigger brains smarter than those with smaller ones? Big people tend to have big brains. Are football players and basketball players smarter than the rest of us? Men tend to be bigger in general, and to have bigger brains than women. But are they smarter?????

But maybe it is brain size as a proportion of body size. Our brains are about 2% of body weight. A dolphin brain is about 1%, and whale brains come in at around 0.1%. So this might start to make sense. But what about the mouse! It comes in at 3%!! http://www.highnorth.no/library/myths/br-si-bo.htm

So what makes us so special? Maybe God did it. But most scientists would agree that saying God did it is a pretty lame explanation for anything. That’s one reason why most scientists are either atheist or agnostic. (See http://blog.beliefnet.com/roddreher/2010/04/science-vs-religion-what-do-scientists-say.html).

Or maybe it is a special version of the Foxp2 gene that gave us improved brain wiring and speech. People with mutations in this gene have verbal dyspraxia, a severe speech and language disorder. Indeed, some have called this the “language gene”. Chimps have an altered version of this gene, and some suggest that this single difference accounts for a big part of the chimp-human disparity.

Or maybe it was a change in head musculature that allowed our craniums to expand more and accommodate larger brains. It has been shown that humans carry an abnormal version of a muscle myosin gene named Myh16. Stedman has suggested that his resulted in weaker and smaller jaw muscles, which in turn allowed the cranium to expand more and accommodate a bigger brain (http://www.ncbi.nlm.nih.gov/pubmed/15042088).

Or maybe it is related to genes that seem to directly control brain size. People with altered versions of these genes suffer microcephaly, or small heads and brains. One view is that people in general have macrocephaly, or big brains, compared to other species, because of special Homo sapiens versions of these genes. http://www.walshlab.org/

Or maybe we aren’t all that incredibly special at all???? Maybe, again, it is just language and culture that separates us from chimps.