A human relative with no clear place in the family tree
One of the most concrete puzzles comes from Homo naledi, a fossil human relative whose age and evolutionary position are both unresolved [1]. Without a reliable date, it is hard to know whether its mix of features is primitive, advanced, or something in between, and therefore hard to say where it sits relative to australopithecines and early Homo [1]. This is a case where a single unknown, the fossil's age, blocks the interpretation of an entire skeleton.
The broader lesson is that human evolution is not a single clean line. Debates about how humans evolved have been part of the field for decades, and the story shows that different human populations share a common origin rather than arising from separate places [3]. Fossil finds like H. naledi keep that picture unsettled because their placement depends on evidence that is still missing [1].
Which genetic changes built the human brain?
The human brain is the most distinctive product of our evolution, marked by a large expansion in brain size and a highly refined structure [5]. Which genetic changes produced it is a long-standing question that the international scientific community has tried to answer [5]. Researchers have found many human-specific genomic variants and regulatory elements, such as human accelerated regions and human-specific enhancers, that accumulated during evolution [5].
The hard part is connecting a DNA difference to a change in brain development. Genomes are about two meters long but fold into a nucleus only about ten micrometers across, and that three-dimensional folding matters for how cells proliferate and differentiate during development [5]. Establishing a causal link between a sequence difference and a regulatory change in brain development, and working out the molecular mechanism, remains a major challenge [5].
The genetic differences that are hard to read
Many of the genetic differences that make humans distinct from our closest primate relatives have long remained a mystery, and the genetic basis of adaptations between human groups as they spread across the globe is poorly characterized [4]. A large part of the difficulty is that much of the relevant variation lies in noncoding regions, such as cis-regulatory elements, which do not code for proteins but help control when and where genes are expressed [4].
New high-throughput tools are beginning to address this. CRISPR screens can directly perturb regulatory elements to see their effects on gene expression and phenotypes, massively parallel reporter assays can test the regulatory impact of sequence variants, and machine learning can predict regulatory function from sequence alone [4]. Applying these tools across diverse phenotypes, model systems, and ancestries is beginning to change the picture, but the downstream consequences of these variants are still being worked out [4].
When and where did modern humans actually arise?
Even the basic narrative of modern human origins is contested. The traditionally dominant Recent Out of Africa hypothesis, which places modern human origins in Africa and treats humans as closely related to chimpanzees, has faced contradictions and has not been fully verified [2]. A newer framework, the maximum genetic diversity theory, is proposed as addressing long-standing puzzles such as the genetic equidistance phenomenon, which earlier theories misinterpreted [2].
Under this framework, new genomic analyses indicate that humans diverged from the pongid clade roughly 18 million years ago, and the Recent Out of East Asia model of modern human origins, first proposed in 1983, is revisited [2]. The paper reports that independent tests have validated these new hypotheses while challenging prevailing ones [2]. This is a live disagreement rather than a settled result, and it shows that even the broad outline of human origins is still being reexamined.
Sources used in this answer
Human evolution: the many mysteries of Homo naledi
Homo naledi raises unresolved questions about the age of its fossils and where it fits in human evolution.
Revisiting Human Evolution: Insights from an Expanded Framework of Evolutionary Processes
An expanded evolutionary framework is proposed to address contradictions and long-standing mysteries such as genetic equidistance, and it reexamines when and where modern humans originated.
Human evolution: a guide to the debates
Human evolution has been shaped by ongoing debates, and the evidence indicates humans share a common origin rather than descending from separate places.
Massively parallel approaches for characterizing noncoding functional variation in human evolution
The genetic differences underlying uniquely human traits and adaptations between human groups remain poorly characterized, especially in noncoding regulatory regions, and new high-throughput methods are beginning to address them.
Three dimensional genome analysis lightens the mystery of human brain evolution.
Identifying which genetic changes produced the human brain, and linking sequence differences to regulatory changes in brain development, remains a major challenge.