Scientists exploring gene variations in humans ... and goats

“It’s blinking lovely when the Prime Minister stands up and starts talking about genome sequencing – it’s marvellous,” says Professor Russell Snell.

“Coronavirus is the wrong genome for our team, but the fact she’s using those words is putting the language out there. It has considerably helped to normalise the language around genetics.”

Russell, from the School of Biological Sciences (SBS) in the Faculty of Science, is a pioneering geneticist who was part of the team that first identified the Huntington’s gene. Huntington’s Disease is a neurological disorder that leads to extensive loss of control over bodily movement, along with dementia, psychological disturbance and premature death.

Russell is a leader of the Biomedical and Applied Research Group at SBS. He has a long-term interest in finding out how the genes behind the illnesses are inherited – by exploring human gene variations in diseases such as myotonic dystrophy, tuberous sclerosis, Parkinson’s, Alzheimer’s and other neurogenetic conditions.

Recently he and the person he calls his “partner in crime”, Associate Professor Klaus Lehnert, delved into something a little different – goat genes. Russell and Klaus identify high-value dairy goats through genetics. Their work was recognised when they became finalists in the PwC Commercial Impact section of the KiwiNet Research Commercialisation Awards.

Working with the Dairy Goat Co-Operative (DGC) they discovered that goats with the PM-1 gene variant produce up to 20 percent more milk. The finding is significant because goats’ milk is used in infant formula, one of New Zealand’s highest-value export products.

Russell and Klaus had been given three years by the Ministry of Business, Innovation and Employment who provided the funding, to identify the genetic makeup of the best-performing goats. They found the gene variant that produces more milk in the first year of the grant funding. The industry began using their research to create high-producing goat herds within two years. The foray into goat genetics might seem out of left-field for two scientists usually working on the human genome, but both men worked together some years ago for ‘the other dairy industry’.

“I grew up on a farm training school,” says Russell. “But I was voted the least likely person to be a farmer – by me – I was more interested in blowing things up or burning things down.”

He may even have been considered the person least likely to be a geneticist. “I didn’t do any biology at University because I thought it was boring. I did physics and accidentally ended up doing genetics, which is actually like physics.

“It’s all about numbers. And it’s unencumbered with dogma. Same for my work with Klaus – he knows it all biologically. I can imagine stuff with kind of a blank brain really and wonder … Klaus can go ‘yeah that looks interesting’. We are very complementary in how we approach the genetic world. He knows how to do stuff. I don’t know how to do stuff, and vice versa, and we make stuff up. It’s been very successful over the years.”

“Russell is supremely creative,” says Klaus. “He thinks thoughts most biologists never think, mostly because it’s been trained out of them.”

Russell says while their genetic research has focused on human disease, the pair are equally interested in applying their tricks to other species if it is useful for farmers and the economy.

“It’s kind of a balance,” he says. “We live in New Zealand and it’s a primary production country regardless of how we want to view it – it’s farm-based. Now that tourism has been hammered, this research is even more important.

“Our focus is adding value to New Zealand however we can do it. The more wealthy New Zealand can get, then the better the health service we will have, the more options our next generations will have.”  

The University also has a postgraduate dairy school, which might surprise some people.

“There’s probably a historic view that Massey, Lincoln, AgResearch and Waikato were the dominant players in dairy research,” says Klaus. “Now Auckland is up there too and part of that comes down to science – breakthroughs in genetics and genomics are responsible for that.”

“Genetic diversity is what we can do, whether it’s human genetic diversity or animal genetic diversity,” says Russell. “We apply the same philosophy across both. There isn’t enough research money to support us wholly doing human stuff in New Zealand so, like everybody does, we do what we can to make a contribution elsewhere.”

Most of what Russell and Klaus do, with colleague Dr Jessie Jacobsen, is done by sequencing genomes.

“When we’re looking at human disease, this could lead to a new approach to treatment or specialised diagnosis or reproductive options for the family,” says Klaus. “For example, a family can find out the chance of having another child with a particular genetic condition, and consider reproductive options to have a healthy child.”

“For many families who have a child with a condition it’s important to find out that there is a genetic cause,” says Russell. “When we find mutations, many families are just content to know the specific reason. It’s no longer a mystery. People always worry if it was something they caused themselves. When we can say ‘no it was sheer bad luck and nothing that you did’, that’s really helpful.”

Says Klaus: “For many families, it’s better than being sent home and the parents being told, ‘it’s probably nothing you did’. That’s not enough for many people. If they have a child with a disease, they often want certainty.”

“This is where the ethics of genetics, particularly human genetics, matters a lot, and our ethic is that the individual owns their own information,” adds Russell. “Nobody else should own that information other than if they’re sharing it for research and even then it is protected.

“Each family is different and we can’t walk in their shoes. Some people want to know, for instance, whether they carry a mutation present in their wider family, and others don’t want to know. For example, less than half the people who have Huntington’s in the family want to know whether they’re going to get it.”

When a person is being tested for genetic variations, another factor comes into play.

“There’s something called incidental findings,” says Klaus. “These are findings not related to the primary reason for testing and we ask families whether they want to know this information or not.”

The SBS team doesn’t deal directly with patients – the information is conveyed to the medical professional who requested the genetic analysis.

“We stay firmly on the side of the research fence so we don’t deliver results directly to patients,” says Russell. “We collect information, do the sequencing and discover mutations. If we find what we think is a mutation causing a condition, we contact the clinician and more testing takes place.

“Often that will lead to counselling an individual, and you might need to be counselling the family about the implications for the wider family, and it’s not our training to do that.”

Klaus, Russell and Jessie are part of a research network called Minds for Minds. They set it up, with others, to better understand autism spectrum disorder. Using genome sequencing, the scientists can identify the specific DNA variations that are responsible for this and other neurodevelopmental disorders.

An example of one of the research strands undertaken is using the latest genome sequencing technology to look for a genetic diagnosis in children with undiagnosed, rare neurodevelopmental disorders. Twenty families took part in a two-year pilot study to discover the genes responsible for disorders that couldn’t be explained through standard tests. Of the 20 families, researchers discovered the gene or mutation responsible for the condition in 11 individuals.

“As well as that, often we get referred patients with extremely rare and undefined conditions, and other patients who have been put through a normal clinical diagnosis, but have come out the other end with no answer,” says Russell. “We tackle those, particularly in autism or developmental conditions but not limited to those; we look at genetics behind cardiac disease as well.

"We try to relate DNA changes to what we call phenotypes, which includes the clinician’s observations, testing results and whether a DNA variation could cause a disease. We rely on the genome to tell us the story and our ability to read the genome to find what’s different.”

They both say that just because you discover the genetic variant causing a disease, that doesn’t mean it’s the end of the road for the people affected.

“For parents to know ‘why’ is a huge thing, rather than to be left wondering why it happened and whether what happened will happen again,” says Klaus. “So if the incidence is one in eight billion, this is valuable information for families planning to have another baby.”

The information is also hugely beneficial when developing treatments for various conditions.

“There’s a new treatment for cystic fibrosis that works really well but costs an awful lot of money and hasn’t been approved here yet,” says Russell. “It’s small molecule treatments and will absolutely extend people’s lives. The biochemical knowledge for that came out of discovering the cystic fibrosis gene in the 1980s.”

Russell was involved in finding one of the genes that causes tuberous sclerosis, an inherited form of cancer.

“There are treatments for that now based on the understanding of the gene. Treatments are also progressing for Huntington’s and hopefully Alzheimer’s. You need to understand the genetic variants in order to derive a drug to treat them.”

The hope that they can contribute to treatment is what drives the group’s research.

“Discovering existing variants in genes that cause human disease, or have beneficial effects in farm animals, to cure the disease, improve our economic efficiency, or minimise our environmental impact, that’s our objective,” says Russell.

Looking at the list of areas in which Klaus and Russell research – from autism to goats' milk, it’s hard to imagine what their work days look like.

“Research is essentially like operating a lab,” says Klaus. “We’re writing essays, producing data points, getting things ready for what we call interpretation. It’s like running a manufacturing plant that makes three or four or five different models of whatever car. Various things come to various points on various days and we just deal with it.”

– Denise Montgomery