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Abstract By the mid-twentieth century, wolves were nearly extinct in the lower 48 states, with a small number surviving in northern Minnesota. After wolves were placed on the endangered species list in 1973, the northern Minnesota wolf population increased and stabilized by the early 2000s. A wolf trophy hunt was introduced in 2012–2014 and then halted by a court order in December 2014. The Minnesota Department of Natural Resources collected wolf radiotelemetry data for the years 2004–2019. Statistical analysis showed that wolf mortality remained close to constant from 2004 until the initiation of the hunt, and that mortality doubled with the initiation of the first hunting and trapping season in 2012, remaining at a nearly constant elevated level through 2019. Notably, average annual wolf mortality increased from 21.7% before wolf hunting seasons (10.0% by human causes and 11.7% natural causes) to 43.4% (35.8% by human causes and 7.6% natural causes). The fine-grained statistical trend implies that human-caused mortality increased sharply during the hunting seasons, while natural mortality initially dropped. After the hunt’s discontinuation, human-caused mortality remained higher than prior to the hunting seasons throughout the five years of the available after-hunt radiotelemetry data.

A synthetic method for the production of circularized DNA containing expression elements independent of plasmids is presented, taking linear double-stranded DNA fragments which are circularized and purified.

Genome-wide association studies (GWASs) and other computational biology techniques are gradually discovering the causal gene variants that contribute to late-onset human diseases. After more than a decade of genome-wide association study efforts, these can account for only a fraction of the heritability implied by familial studies, the so-called “missing heritability” problem. Computer simulations of polygenic late-onset diseases (LODs) in an aging population have quantified the risk allele frequency decrease at older ages caused by individuals with higher polygenic risk scores (PRSs) becoming ill proportionately earlier. This effect is most prominent for diseases characterized by high cumulative incidence and high heritability, examples of which include Alzheimer’s disease, coronary artery disease, cerebral stroke, and type 2 diabetes. The incidence rate for LODs grows exponentially for decades after early onset ages, guaranteeing that the cohorts used for GWASs overrepresent older individuals with lower PRSs, whose disease cases are disproportionately due to environmental causes such as old age itself. This mechanism explains the decline in clinical predictive power with age and the lower discovery power of familial studies of heritability and GWASs. It also explains the relatively constant-with-age heritability found for LODs of lower prevalence, exemplified by cancers.

With the accumulation of scientific knowledge of the genetic causes of common diseases and continuous advancement of gene-editing technologies, gene therapies to prevent polygenic diseases may soon become possible. This study endeavored to assess population genetics consequences of such therapies. Computer simulations were used to evaluate the heterogeneity in causal alleles for polygenic diseases that could exist among geographically distinct populations. The results show that although heterogeneity would not be easily detectable by epidemiological studies following population admixture, even significant heterogeneity would not impede the outcomes of preventive gene therapies. Preventive gene therapies designed to correct causal alleles to a naturally-occurring neutral state of nucleotides would lower the prevalence of polygenic early- to middle-age-onset diseases in proportion to the decreased population relative risk attributable to the edited alleles. The outcome would manifest differently for late-onset diseases, for which the therapies would result in a delayed disease onset and decreased lifetime risk; however, the lifetime risk would increase again with prolonging population life expectancy, which is a likely consequence of such therapies. If the preventive heritable gene therapies were to be applied on a large scale, the decreasing frequency of risk alleles in populations would reduce the disease risk or delay the age of onset, even with a fraction of the population receiving such therapies. With ongoing population admixture, all groups would benefit over generations.

Gene therapy techniques and genetic knowledge may sufficiently advance, within the next few decades, to support prophylactic gene therapy for the prevention of polygenic late-onset diseases. The risk of these diseases may, hypothetically, be lowered by correcting the effects of a subset of common low effect gene variants. In this paper, simulations show that if such gene therapy were to become technically possible; and if the incidences of the treated diseases follow the proportional hazards model with a multiplicative genetic architecture composed of a sufficient number of common small effect gene variants, then: (a) late-onset diseases with the highest familial heritability will have the largest number of variants available for editing; (b) diseases that currently have the highest lifetime risk, particularly those with the highest incidence rate continuing into older ages, will prove the most challenging cases in lowering lifetime risk and delaying the age of onset at a population-wide level; (c) diseases that are characterized by the lowest lifetime risk will show the strongest and longest-lasting response to such therapies; and (d) longer life expectancy is associated with a higher lifetime risk of these diseases, and this tendency, while delayed, will continue after therapy.